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1. Bone marrow monocytes sustain NK cell-poiesis during non-alcoholic steatohepatitis

Author

Elsa Bourayou, Thibaut Perchet, Sylvain Meunier, Hugo Bouvier, Marie-Pierre Mailhe, Evie Melanitou, Ana Cumano, and Rachel Golub

Subjects
CP: Immunology, Biology (General), QH301-705.5
Abstract

Summary: Natural killer (NK) cells are the predominant lymphocyte population in the liver. At the onset of non-alcoholic steatohepatitis (NASH), an accumulation of activated NK cells is observed in the liver in parallel with inflammatory monocyte recruitment and an increased systemic inflammation. Using in vivo and in vitro experiments, we unveil a specific stimulation of NK cell-poiesis during NASH by medullary monocytes that trans-present interleukin-15 (IL-15) and secrete osteopontin, a biomarker for patients with NASH. This cellular dialogue leads to increased survival and maturation of NK precursors that are recruited to the liver, where they dampen the inflammatory monocyte infiltration. The increase in the production of both osteopontin and the IL-15/IL-15Rα complex by bone marrow monocytes is induced by endotoxemia. We propose a tripartite gut-liver-bone marrow axis regulating the immune population dynamics and effector functions during liver inflammation.

Published
2024
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3. Inflammatory-driven NK cell maturation and its impact on pathology

Author

Elsa Bourayou and Rachel Golub

Subjects
NK cells, bone marrow, development, maturation, inflammation, Immunologic diseases. Allergy, RC581-607
Abstract

NK cells are innate lymphocytes involved in a large variety of contexts and are crucial in the immunity to intracellular pathogens as well as cancer due to their ability to kill infected or malignant cells. Thus, they harbor a strong potential for clinical and therapeutic use. NK cells do not require antigen exposure to get activated; their functional response is rather based on a balance between inhibitory/activating signals and on the diversity of germline-encoded receptors they express. In order to reach optimal functional status, NK cells go through a step-wise development in the bone marrow before their egress, and dissemination into peripheral organs via the circulation. In this review, we summarize bone marrow NK cell developmental stages and list key factors involved in their differentiation before presenting newly discovered and emerging factors that regulate NK cell central and peripheral maturation. Lastly, we focus on the impact inflammatory contexts themselves can have on NK cell development and functional maturation.

Published
2022
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4. The Notch signaling pathway involvement in innate lymphoid cell biology

Author

Rachel Golub

Subjects
Notch pathway, Development of lymphoid cells, ILC, Immune functions, Polarization of immune subsets, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

The role of Notch in the immune system was first described in the late 90s. Reports revealed that Notch is one of the most conserved developmental pathways involved in diverse biological processes such as the development, differentiation, survival and functions of many immune populations. Here, we provide an extended view of the pleiotropic effects of the Notch signaling on the innate lymphoid cell (ILC) biology. We review the current knowledge on Notch signaling in the regulation of ILC differentiation, plasticity and functions in diverse tissue types and at both the fetal and adult developmental stages. ILCs are early responder cells that secrete a large panel of cytokines after stimulation. By controlling the abundance of ILCs and the specificity of their release, the Notch pathway is also implicated in the regulation of their functions. The Notch pathway is therefore an important player in both ILC cell fate decision and ILC immune response.

Published
2021
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5. Signaling Pathways Tuning Innate Lymphoid Cell Response to Hepatocellular Carcinoma

Author

Elsa Bourayou and Rachel Golub

Subjects
HCC, NASH, NK cells, ILC1, liver, inflammation, Immunologic diseases. Allergy, RC581-607
Abstract

Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide and its incidence continues to rise globally. Various causes can lead to its development such as chronic viral infections causing hepatitis, cirrhosis or nonalcoholic steatohepatitis (NASH). The contribution of immune cells to HCC development and progression has been extensively studied when it comes to adaptive lymphocytes or myeloid populations. However, the role of the innate lymphoid cells (ILCs) is still not well defined. ILCs are a family of lymphocytes comprising five subsets including circulating Natural Killer (NK) cells, ILC1s, ILC2s, ILC3s and lymphocytes tissue-inducer cells (LTi). Mostly located at epithelial surfaces, tissue-resident ILCs and NK cells can rapidly react to environmental changes to mount appropriate immune responses. Here, we provide an overview of their roles and actions in HCC with an emphasis on the importance of diverse signaling pathways (Notch, TGF-β, Wnt/β-catenin…) in the tuning of their response to HCC.

Published
2022
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6. CXCR6 deficiency impairs cancer vaccine efficacy and CD8+ resident memory T-cell recruitment in head and neck and lung tumors

Author

Diane Damotte, Nadine BenHamouda, Ludger Johannes, Estelle Dransart, Eric Tartour, Emmanuel Donnadieu, Léa Paolini, Fathia Mami-Chouaib, Charlotte Blanc, Sebastian Kobold, Soumaya Karaki, Thi Tran, Isabelle Galy-Fauroux, Alice Mougel, Marie Anson, Corinne Tanchot, Nadege Gruel, Laure Gibault, Francoise Lepimpec-Barhes, Elizabeth Fabre, Cecile Badoual, and Rachel Golub

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Resident memory T lymphocytes (TRM) are located in tissues and play an important role in immunosurveillance against tumors. The presence of TRM prior to treatment or their induction is associated to the response to anti-Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1) immunotherapy and the efficacy of cancer vaccines. Previous work by our group and others has shown that the intranasal route of vaccination allows more efficient induction of these cells in head and neck and lung mucosa, resulting in better tumor protection. The mechanisms of in vivo migration of these cells remains largely unknown, apart from the fact that they express the chemokine receptor CXCR6.Methods We used CXCR6-deficient mice and an intranasal tumor vaccination model targeting the Human Papillomavirus (HPV) E7 protein expressed by the TC-1 lung cancer epithelial cell line. The role of CXCR6 and its ligand, CXCL16, was analyzed using multiparametric cytometric techniques and Luminex assays.Human biopsies obtained from patients with lung cancer were also included in this study.Results We showed that CXCR6 was preferentially expressed by CD8+ TRM after vaccination in mice and also on intratumoral CD8+ TRM derived from human lung cancer. We also demonstrate that vaccination of Cxcr6-deficient mice induces a defect in the lung recruitment of antigen-specific CD8+ T cells, preferentially in the TRM subsets. In addition, we found that intranasal vaccination with a cancer vaccine is less effective in these Cxcr6-deficient mice compared with wild-type mice, and this loss of efficacy is associated with decreased recruitment of local antitumor CD8+ TRM. Interestingly, intranasal, but not intramuscular vaccination induced higher and more sustained concentrations of CXCL16, compared with other chemokines, in the bronchoalveolar lavage fluid and pulmonary parenchyma.Conclusions This work demonstrates the in vivo role of CXCR6-CXCL16 axis in the migration of CD8+ resident memory T cells in lung mucosa after vaccination, resulting in the control of tumor growth. This work reinforces and explains why the intranasal route of vaccination is the most appropriate strategy for inducing these cells in the head and neck and pulmonary mucosa, which remains a major objective to overcome resistance to anti-PD-1/PD-L1, especially in cold tumors.

Published
2021
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7. Distinct Waves from the Hemogenic Endothelium Give Rise to Layered Lymphoid Tissue Inducer Cell Ontogeny

Author

Milesa Simic, Iris Manosalva, Lionel Spinelli, Rebecca Gentek, Raheleh R. Shayan, Carole Siret, Mathilde Girard-Madoux, Shuaiwei Wang, Lauriane de Fabritus, Janneke Verschoor, Yann M. Kerdiles, Marc Bajenoff, Ralf Stumm, Rachel Golub, and Serge A. van de Pavert

Subjects
Hematopoiesis, Innate Lymphoid Cell, ILC, LTi, Cxcr4, Cdh5, Biology (General), QH301-705.5
Abstract

Summary: During embryogenesis, lymphoid tissue inducer (LTi) cells are essential for lymph node organogenesis. These cells are part of the innate lymphoid cell (ILC) family. Although their earliest embryonic hematopoietic origin is unclear, other innate immune cells have been shown to be derived from early hemogenic endothelium in the yolk sac as well as the aorta-gonad-mesonephros. A proper model to discriminate between these locations was unavailable. In this study, using a Cxcr4-CreERT2 lineage tracing model, we identify a major contribution from embryonic hemogenic endothelium, but not the yolk sac, toward LTi progenitors. Conversely, embryonic LTi cells are replaced by hematopoietic stem cell-derived cells in adults. We further show that, in the fetal liver, common lymphoid progenitors differentiate into highly dynamic alpha-lymphoid precursor cells that, at this embryonic stage, preferentially mature into LTi precursors and establish their functional LTi cell identity only after reaching the periphery.

Published
2020
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8. Natural Killer Cells and Type 1 Innate Lymphoid Cells Are New Actors in Non-alcoholic Fatty Liver Disease

Author

Carmelo Luci, Elodie Vieira, Thibaut Perchet, Philippe Gual, and Rachel Golub

Subjects
NAFLD, NASH, NK cells, ILC1, liver, inflammation, Immunologic diseases. Allergy, RC581-607
Abstract

Obesity and associated liver diseases (Non Alcoholic Fatty Liver Disease, NAFLD) are a major public health problem with increasing incidence in Western countries (25% of the affected population). These complications develop from a fatty liver (steatosis) to an inflammatory state (steatohepatitis) evolving toward fibrosis and hepatocellular carcinoma. Lipid accumulation in the liver contributes to hepatocyte cell death and promotes liver injury. Local immune cells are activated either by Danger Associated Molecular Patterns (DAMPS) released by dead hepatocytes or by bacterial products (PAMPS) reaching the liver due to increased intestinal permeability. The resulting low-grade inflammatory state promotes the progression of liver complications toward more severe grades. Innate lymphoid cells (ILC) are an heterogeneous family of five subsets including circulating Natural Killer (NK) cells, ILC1, ILC2, ILC3, and lymphocytes tissue-inducer cells (LTi). NK cells and tissue-resident ILCs, mainly located at epithelial surfaces, are prompt to rapidly react to environmental changes to mount appropriate immune responses. Recent works have demonstrated the interplay between ILCs subsets and the environment within metabolic active organs such as liver, adipose tissue and gut during diet-induced obesity leading or not to hepatic abnormalities. Here, we provide an overview of the newly roles of NK cells and ILC1 in metabolism focusing on their contribution to the development of NAFLD. We also discuss recent studies that demonstrate the ability of these two subsets to influence tissue-specific metabolism and how their function and homeostasis are affected during metabolic disorders.

Published
2019
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9. Single-Cell Gene Expression Analyses Reveal Heterogeneous Responsiveness of Fetal Innate Lymphoid Progenitors to Notch Signaling

Author

Sylvestre Chea, Sandrine Schmutz, Claire Berthault, Thibaut Perchet, Maxime Petit, Odile Burlen-Defranoux, Ananda W. Goldrath, Hans-Reimer Rodewald, Ana Cumano, and Rachel Golub

Subjects
Biology (General), QH301-705.5
Abstract

T and innate lymphoid cells (ILCs) share some aspects of their developmental programs. However, although Notch signaling is strictly required for T cell development, it is dispensable for fetal ILC development. Constitutive activation of Notch signaling, at the common lymphoid progenitor stage, drives T cell development and abrogates ILC development by preventing Id2 expression. By combining single-cell transcriptomics and clonal culture strategies, we characterize two heterogeneous α4β7-expressing lymphoid progenitor compartments. αLP1 (Flt3+) still retains T cell potential and comprises the global ILC progenitor, while αLP2 (Flt3−) consists of ILC precursors that are primed toward the different ILC lineages. Only a subset of αLP2 precursors is sensitive to Notch signaling required for their proliferation. Our study identifies, in a refined manner, the diversity of transitional stages of ILC development, their transcriptional signatures, and their differential dependence on Notch signaling.

Published
2016
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10. Maintenance of Type 2 Response by CXCR6-Deficient ILC2 in Papain-Induced Lung Inflammation

Author

Sylvain Meunier, Sylvestre Chea, Damien Garrido, Thibaut Perchet, Maxime Petit, Ana Cumano, and Rachel Golub

Subjects
immunology, ilc immunity, cxcr6, lung inflammation, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Innate lymphoid cells (ILC) are important players of early immune defenses in situations like lymphoid organogenesis or in case of immune response to inflammation, infection and cancer. Th1 and Th2 antagonism is crucial for the regulation of immune responses, however mechanisms are still unclear for ILC functions. ILC2 and NK cells were reported to be both involved in allergic airway diseases and were shown to be able to interplay in the regulation of the immune response. CXCR6 is a common chemokine receptor expressed by all ILC, and its deficiency affects ILC2 and ILC1/NK cell numbers and functions in lungs in both steady-state and inflammatory conditions. We determined that the absence of a specific ILC2 KLRG1+ST2− subset in CXCR6-deficient mice is probably dependent on CXCR6 for its recruitment to the lung under inflammation. We show that despite their decreased numbers, lung CXCR6-deficient ILC2 are even more activated cells producing large amount of type 2 cytokines that could drive eosinophilia. This is strongly associated to the decrease of the lung Th1 response in CXCR6-deficient mice.

Published
2019
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11. The Notch Signaling Pathway Is Balancing Type 1 Innate Lymphoid Cell Immune Functions

Author

Thibaut Perchet, Maxime Petit, Elena-Gaia Banchi, Sylvain Meunier, Ana Cumano, and Rachel Golub

Subjects
Notch, innate lymphoid cells, liver, cancer, inflammation, transcription factors, Immunologic diseases. Allergy, RC581-607
Abstract

The Notch pathway is one of the canonical signaling pathways implicated in the development of various solid tumors. During carcinogenesis, the Notch pathway dysregulation induces tumor expression of Notch receptor ligands participating to escape the immune surveillance. The Notch pathway conditions both the development and the functional regulation of lymphoid subsets. Its importance on T cell subset polarization has been documented contrary to its action on innate lymphoid cells (ILC). We aim to analyze the effect of the Notch pathway on type 1 ILC polarization and functions after disruption of the RBPJk-dependent Notch signaling cascade. Indeed, type 1 ILC comprises conventional NK (cNK) cells and type 1 helper innate lymphoid cells (ILC1) that share Notch-related functional characteristics such as the IFNg secretion downstream of T-bet expression. cNK cells have strong antitumor properties. However, data are controversial concerning ILC1 functions during carcinogenesis with models showing antitumoral capacities and others reporting ILC1 inability to control tumor growth. Using various mouse models of Notch signaling pathway depletion, we analyze the effects of its absence on type 1 ILC differentiation and cytotoxic functions. We also provide clues into its role in the maintenance of immune homeostasis in tissues. We show that modulating the Notch pathway is not only acting on tumor-specific T cell activity but also on ILC immune subset functions. Hence, our study uncovers the intrinsic Notch signaling pathway in ILC1/cNK populations and their response in case of abnormal Notch ligand expression. This study help evaluating the possible side effects mediated by immune cells different from T cells, in case of multivalent forms of the Notch receptor ligand delta 1 treatments. In definitive, it should help determining the best novel combination of therapeutic strategies in case of solid tumors.

Published
2018
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12. CXCR6 Expression Is Important for Retention and Circulation of ILC Precursors

Author

Sylvestre Chea, Cécilie Possot, Thibaut Perchet, Maxime Petit, Ana Cumano, and Rachel Golub

Subjects
Pathology, RB1-214
Abstract

Innate lymphoid cells are present at mucosal sites and represent the first immune barrier against infections, but what contributes to their circulation and homing is still unclear. Using Rag2−/−Cxcr6Gfp/+ reporter mice, we assessed the expression and role of CXCR6 in the circulation of ILC precursors and their progeny. We identify CXCR6 expressing ILC precursors in the bone marrow and characterize their significant increase in CXCR6-deficient mice at steady state, indicating their partial retention in the bone marrow after CXCR6 ablation. Circulation was also impaired during embryonic life as fetal liver from CXCR6-deficient embryos displayed decreased numbers of ILC3 precursors. When injected, fetal CXCR6-deficient ILC3 precursors also fail to home and reconstitute ILC compartments in vivo. We show that adult intestinal ILC subsets have heterogeneous expression pattern of CXCR6, integrin α4β7, CD62L, CD69, and CD44, with ILC1 and ILC3 being more likely tissue resident lymphocytes. Intestinal ILC subsets were unchanged in percentages and numbers in both mice. We demonstrate that the ILC frequency is maintained due to a significant increase of ILC peripheral proliferation, as well as an increased proliferation of the in situ ILC precursors to compensate their retention in the bone marrow.

Published
2015
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13. Supplemental Table S2 from Osteogenic Potential of Mesenchymal Stromal Cells Contributes to Primary Myelofibrosis

Author

Marie-Caroline Le Bousse-Kerdilès, Jean-Jacques Lataillade, Alessandro M. Vannucchi, Marie-Françoise Bourgeade, Jean-Christophe Ianotto, Brigitte Dupriez, Thierry de Revel, Jean-Baptiste Souraud, Olivier Pierre-Louis, Emilie Henault, Patricia Albanese, Nathalie Rochet, Bernadette Guerton, Adrienne Anginot, Sandrine Schmutz, Rachel Golub, Frédéric Torossian, Lisa Pieri, Johanna Konopacki, Christophe Desterke, and Christophe Martinaud

Abstract

Hematopoiesis support by MSCs in LTBMC BFU-E, CFU-G, CFU-M and CFU-GM by PMF (n=3) and healthy donors (HD, n=3) expressed as number of colonies for 104 bone marrow mononuclear cells.

Published
2023

14. Synergistic prostaglandin E synthesis by myeloid and endothelial cells promotes fetal hematopoietic stem cell expansion in vertebrates

Author

Pietro Cacialli, Marie‐Pierre Mailhe, Ingrid Wagner, Doron Merkler, Rachel Golub, Julien Y Bertrand, Université de Genève = University of Geneva (UNIGE), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), RG work is supported by Institut Pasteur, Institut National de la Santé et de la Recherche Médicale, Université de Paris, and ANR project NASHILCCD8 (#18-CE15-0024-01). JYB is funded by the Swiss National Fund (310030_184814). DM is funded by the Swiss National Fund (310030B_201271). Open access funding provided by Universite de Geneve., ANR-18-CE15-0024,NASHILCCD8,Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome.(2018), Vougny, Marie-Christine, APPEL À PROJETS GÉNÉRIQUE 2018 - Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome. - - NASHILCCD82018 - ANR-18-CE15-0024 - AAPG2018 - VALID, Cacialli P., Mailhe M.-P., Wagner I., Merkler D., Golub R., and Bertrand J.Y.

Subjects
General Immunology and Microbiology, [SDV.IMM] Life Sciences [q-bio]/Immunology, slco2b1, Animal, Hemangioblasts, General Neuroscience, Hematopoietic Stem Cell, HSC, Hemangioblast, Hematopoietic Stem Cells, General Biochemistry, Genetics and Molecular Biology, Dinoprostone, Mice, hematopoietic niche, HSCs, Animals, Prostaglandin H2, [SDV.IMM]Life Sciences [q-bio]/Immunology, PGE2, Molecular Biology, Zebrafish
Abstract

International audience; During development, hematopoietic stem cells (HSCs) are produced from the hemogenic endothelium and will expand in a transient hematopoietic niche. Prostaglandin E2 (PGE2) is essential during vertebrate development and HSC specification, but its precise source in the embryo remains elusive. Here, we show that in the zebrafish embryo, PGE2 synthesis genes are expressed by distinct stromal cell populations, myeloid (neutrophils, macrophages), and endothelial cells of the caudal hematopoietic tissue. Ablation of myeloid cells, which produce the PGE2 precursor prostaglandin H2 (PGH2), results in loss of HSCs in the caudal hematopoietic tissue, which could be rescued by exogeneous PGE2 or PGH2 supplementation. Endothelial cells contribute by expressing the PGH2 import transporter slco2b1 and ptges3, the enzyme converting PGH2 into PGE2. Of note, differential niche cell expression of PGE2 biosynthesis enzymes is also observed in the mouse fetal liver. Taken altogether, our data suggest that the triad composed of neutrophils, macrophages, and endothelial cells sequentially and synergistically contributes to blood stem cell expansion during vertebrate development.

Published
2022

15. Mechanisms Underlying Mait Cell Ability to Promote Skin Wound Repair

Author

Anastasia Du Halgouet, Aurélie Darbois, Mansour Alkobtawi, Martin Mestdagh, Aurélia Alphonse, Virginie Premel, Dietmar Zeiss, Yara El Morr, Hélène Bugaut, François Legoux, Laetitia Perrin, Selim Aractingi, Rachel Golub, Olivier Lantz, and Marion Salou

Subjects
History, Polymers and Plastics, Business and International Management, Industrial and Manufacturing Engineering
Published
2022

16. Macrophage‐fibroblast circuits in the spleen

Author

Rachel Golub, Alicia Bellomo, Marc Bajénoff, Rebecca Gentek, Trafic Vésiculaire, Réponse Innée et Virus – Vesicular trafficking, Innate response, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Edinburgh, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This review was funded by grants from the Agence National pour la Recherche (ANR-17-CE15-0015-01), the Fondation pour la Recherche Médicale (FRM : FDT201904007871), the University of Edinburgh, the Kennedy Trust for Rheumatology Research (KENN 19 20 07) and from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program grant agreement 647257- STROMA. This work was supported by institutional grants from INSERM, CNRS, and Aix-Marseille University to the CIML., ANR-17-CE15-0015,StroMAC,Cross-talk des macrophages et du stroma au sein du ganglion lymphatique(2017), European Project: 647257,H2020,ERC-2014-CoG,STROMA(2015), Vougny, Marie-Christine, Cross-talk des macrophages et du stroma au sein du ganglion lymphatique - - StroMAC2017 - ANR-17-CE15-0015 - AAPG2017 - VALID, IMMUNOBIOLOGY OF LYMPHOID STROMAL CELLS - STROMA - - H20202015-10-01 - 2020-09-30 - 647257 - VALID, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
0301 basic medicine, Stromal cell, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Niche, Spleen, macrophage, Biology, Leukocyte Count, 03 medical and health sciences, 0302 clinical medicine, Stroma, Immunity, medicine, Homeostasis, Humans, Immunology and Allergy, Macrophage, Aged, Macrophages, Fibroblasts, stromal cell, Cell biology, Crosstalk (biology), niche, 030104 developmental biology, Lymphatic system, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, spleen, 030215 immunology
Abstract

International audience; Macrophages are an integral part of all organs in the body, where they contribute to immune surveillance, protection, and tissue-specific homeostatic functions. This is facilitated by so-called niches composed of macrophages and their surrounding stroma. These niches structurally anchor macrophages and provide them with survival factors and tissue-specific signals that imprint their functional identity. In turn, macrophages ensure appropriate functioning of the niches they reside in. Macrophages thus form reciprocal, mutually beneficial circuits with their cellular niches. In this review, we explore how this concept applies to the spleen, a large secondary lymphoid organ whose primary functions are to filter the blood and regulate immunity. We first outline the splenic micro-anatomy, the different populations of splenic fibroblasts and macrophages and their respective contribution to protection of and key physiological processes occurring in the spleen. We then discuss firmly established and potential cellular circuits formed by splenic macrophages and fibroblasts, with an emphasis on the molecular cues underlying their crosstalk and their relevance to splenic functionality. Lastly, we conclude by considering how these macrophage-fibroblast circuits might be impaired by aging, and how understanding these changes might help identify novel therapeutic avenues with the potential of restoring splenic functions in the elderly.

Published
2021

17. Myeloid and endothelial cells cooperate to promote hematopoietic stem cells expansion in the fetal niche

Author

Mailhe M, Rachel Golub, Pietro Cacialli, and Julien Y. Bertrand

Subjects
Hemogenic endothelium, Cell type, Haematopoiesis, Myeloid, medicine.anatomical_structure, Hematopoietic Tissue, Mesenchymal stem cell, medicine, lipids (amino acids, peptides, and proteins), Stem cell, Biology, Embryonic stem cell, Cell biology
Abstract

During embryonic development, very few hematopoietic stem cells (HSCs) are produced from the hemogenic endothelium, that will be expanded in a very specific niche. This fetal HSC niche comprises a complex and dynamic molecular network of interactions between multiple cell types, including endothelial cells (ECs) and mesenchymal stromal cells. It is known that functional changes in the hematopoietic niche, such as aging, vascular cell remodelling or inflammation can directly affect HSCs. Among all these inflammatory regulators, the eicosanoid prostaglandin E (PGE2) has been shown to be very important during embryonic life. However, the precise source of PGE2 in the embryo is still elusive. Here we show that all the genes involved in PGE2 synthesis and transport are expressed by distinct cells of the caudal hematopoietic tissue (CHT) in the zebrafish embryo and in the mouse fetal liver, suggesting that each cell type acts sequentially and collaboratively with the others to produce PGE2 and ultimately expand HSCs. Among these cells, we found myeloid cells (both neutrophils and macrophages) to be absolutely necessary, as they concur to the production of PGH2, the precursor of PGE2. To measure the impact of myeloid cells, we generated a genetic model of myeloid ablation, which caused a loss of HSCs in the CHT, that could be rescued by supplementing zebrafish embryos with PGE2 or PGH2. ECs expressed the slco2b1 transporter to import PGH2, and ptges3, the necessary enzyme to convert this latter into PGE2. Taken altogether, our data show that the triad composed of neutrophils, macrophages and ECs concurs to HSC expansion in the CHT.

Published
2021

18. A wave of bipotent T/ILC-restricted progenitors shapes the embryonic thymus microenvironment in a time-dependent manner

Author

Ana Cumano, Elisa Gomez Perdiguero, Pablo Pereira, Rachel Golub, Paulo Vieira, Laina Freyer, Ramy Elsaid, Odile Burlen-Defranoux, Francisca Soares-da-Silva, Thibaut Perchet, Antonio Bandeira, Sylvain Meunier, Lorea Iturri, Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto = University of Porto, Macrophages et Cellules endothéliales / Macrophages and Endothelial Cells, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Cellule Pasteur UPMC, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP), This work was financed by the Institut Pasteur, INSERM, Pasteur-Weizmann Foundation and ANR (grant Twothyme and Epi-Dev) through grants to A.C., by REVIVE (Investissement d'Avenir, ANR-10-LABX-73)to A.C. and R.E., by recurrent funding from the Institut Pasteur, the CNRS, Revive (Investissement d'Avenir, ANR-10-LABX-73) and by an ERC investigator award (2016-StG-715320) from the European Research Council to E.G.P., ANR-14-CE11-0022,Twothyme,Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T.(2014), ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Universidade do Porto, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris], Vougny, Marie-Christine, Appel à projets générique - Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T. - - Twothyme2014 - ANR-14-CE11-0022 - Appel à projets générique - VALID, and Laboratoires d'excellence - Stem Cells in Regenerative Biology and Medicine - - REVIVE2010 - ANR-10-LABX-0073 - LABX - VALID

Subjects
0303 health sciences, education.field_of_study, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Population, Hematopoietic stem cell, Cell Biology, Hematology, Biology, Biochemistry, Embryonic stem cell, Cell biology, 03 medical and health sciences, Haematopoiesis, 0302 clinical medicine, Lymphatic system, Immune system, medicine.anatomical_structure, medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Lymphopoiesis, Progenitor cell, education, 030304 developmental biology, 030215 immunology
Abstract

During embryonic development, multiple waves of hematopoietic progenitors with distinct lineage potential are differentially regulated in time and space. Two different waves of thymic progenitors colonize the fetal thymus where they contribute to thymic organogenesis and homeostasis. The origin, the lineage differentiation potential of the first wave, and their relative contribution in shaping the thymus architecture, remained, however, unclear. Here, we show that the first wave of thymic progenitors comprises a unique population of bipotent T and innatel lymphoid cells (T/ILC), generating a lymphoid tissue inducer cells (LTi's), in addition to invariant Vγ5+ T cells. Transcriptional analysis revealed that innate lymphoid gene signatures and, more precisely, the LTi-associated transcripts were expressed in the first, but not in the second, wave of thymic progenitors. Depletion of early thymic progenitors in a temporally controlled manner showed that the progeny of the first wave is indispensable for the differentiation of autoimmune regulator–expressing medullary thymic epithelial cells (mTECs). We further show that these progenitors are of strict hematopoietic stem cell origin, despite the overlap between lymphopoiesis initiation and the transient expression of lymphoid-associated transcripts in yolk sac (YS) erythromyeloid-restricted precursors. Our work highlights the relevance of the developmental timing on the emergence of different lymphoid subsets, required for the establishment of a functionally diverse immune system.

Published
2021
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19. The interplay between innate lymphoid cells and T cells

Author

Gayetri Ramachandran, Rachel Golub, Marie Cherrier, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), M.C. is supported by INSERM and Association François Aupetit dedicated to patients suffering from IBD. R.G. work is supported by Institut Pasteur, Institut National de la Santé et de la Recherche Médicale, Université de Paris, and ANR project NASHILCCD8 (#18-CE15-0024-01)., We thank Serge van de Pavert for critical discussions and for review of the paper., ANR-18-CE15-0024,NASHILCCD8,Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome.(2018), Vougny, Marie-Christine, APPEL À PROJETS GÉNÉRIQUE 2018 - Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome. - - NASHILCCD82018 - ANR-18-CE15-0024 - AAPG2018 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)

Subjects
0301 basic medicine, Cell type, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Context (language use), Cell Communication, Biology, Gut flora, Adaptive Immunity, Lymphocyte Activation, Substrate Specificity, Immunomodulation, 03 medical and health sciences, 0302 clinical medicine, Immune system, T-Lymphocyte Subsets, Immunology and Allergy, Animals, Humans, skin and connective tissue diseases, Immunity, Cellular, Innate lymphoid cell, Cell Differentiation, Acquired immune system, biology.organism_classification, Immunity, Innate, body regions, 030104 developmental biology, Gene Expression Regulation, Host-Pathogen Interactions, [SDV.IMM]Life Sciences [q-bio]/Immunology, Neuroscience, Immunologic Memory, Function (biology), Homeostasis, Biomarkers, 030215 immunology, Signal Transduction
Abstract

International audience; ILCs and T cells are closely related functionally but they significantly differ in their ability to circulate, expand, and renew. Cooperation and reciprocal functional regulation suggest that these cell types are more complementary than simply redundant during immune responses. How ILCs shape T-cell responses is strongly dependent on the tissue and inflammatory context. Likewise, indirect regulation of ILCs by adaptive immunity is induced by environmental cues such as the gut microbiota. Here, we review shared requirements for the development and function of both cell types and divergences in the orchestration of prototypic immune functions. We discuss the diversity of functional interactions between T cells and ILCs during homeostasis and immune responses. Identifying the location and the nature of the tissue microenvironment in which these interactions are taking place may uncover the remaining mysteries of their close encounters.

Published
2020

20. Tbet promotes CXCR6 expression in immature natural killer cells and natural killer cell egress from the bone marrow

Author

Antonia O. Cuff, Thibaut Perchet, Simone Dertschnig, Rachel Golub, Victoria Male, Imperial College London, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), University College of London [London] (UCL), This work was funded by Royal Society/Wellcome Trust Sir Henry Dale Fellowship WT105677 (VM and AC) and an Agence Nationale de la Recherche ANR Grant 8_CE15‐0024‐01 (RG and TP)., Vougny, Marie-Christine, and Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
bone marrow, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Cell, Bone Marrow Cells, Spleen, Biology, migration, Natural killer cell, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, medicine, Animals, Immunology and Allergy, Progenitor cell, Bone Marrow Transplantation, Receptors, CXCR6, 030304 developmental biology, Mice, Knockout, 0303 health sciences, S1PR5, natural killer cells, Innate lymphoid cell, Original Articles, Hematopoietic Stem Cells, Phenotype, CXCR6, Cell biology, Killer Cells, Natural, Mice, Inbred C57BL, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, Original Article, Bone marrow, T-Box Domain Proteins, 030215 immunology, Tbet
Abstract

Summary Tbet‐deficient mice have reduced natural killer (NK) cells in blood and spleen, but increased NK cells in bone marrow and lymph nodes, a phenotype that is thought to be the result of defective migration. Here, we revisit the role of Tbet in NK cell bone marrow egress. We definitively show that the accumulation of NK cells in the bone marrow of Tbet‐deficient Tbx21 −/− animals occurs because of a migration defect and identify a module of genes, co‐ordinated by Tbet, which affects the localization of NK cells in the bone marrow. Cxcr6 is approximately 125‐fold underexpressed in Tbx21 −/−, compared with wild‐type, immature NK cells. Immature NK cells accumulate in the bone marrow of CXCR6‐deficient mice, and CXCR6‐deficient progenitors are less able to reconstitute the peripheral NK cell compartment than their wild‐type counterparts. However, the CXCR6 phenotype is largely confined to immature NK cells, whereas the Tbet phenotype is present in both immature and mature NK cells, suggesting that genes identified as being more differentially expressed in mature NK cells, such as S1pr5, Cx3cr1, Sell and Cd69, may be the major drivers of the phenotype., Here, we definitively show that the accumulation of NK cells in the bone marrow of Tbet‐deficient Tbx21 −/− animals occurs because of a migration defect and identify a module of genes, co‐ordinated by Tbet, which affects the localization of NK cells in the bone marrow.

Published
2020

21. Distinct Waves from the Hemogenic Endothelium Give Rise to Layered Lymphoid Tissue Inducer Cell Ontogeny

Author

Mathilde J. H. Girard-Madoux, Yann M. Kerdiles, Rebecca Gentek, Lionel Spinelli, Raheleh R. Shayan, Carole Siret, Milesa Simic, Rachel Golub, Janneke Verschoor, Marc Bajénoff, Serge A. van de Pavert, Lauriane de Fabritus, Ralf Stumm, Iris Manosalva, Shuaiwei Wang, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Jena University Hospital [Jena], Lymphopoïèse, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), van de Pavert, Serge, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-17-CE13-0029,ATTRACT,L'attraction et le rôle des cellules immunitaires innées dans les lésions cérébrales.(2017)

Subjects
0301 basic medicine, Receptors, CXCR4, [SDV.IMM] Life Sciences [q-bio]/Immunology, Hemangioblasts, Lymphoid Tissue, Embryonic Development, Biology, General Biochemistry, Genetics and Molecular Biology, Cxcr4, 03 medical and health sciences, 0302 clinical medicine, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, Animals, Humans, Lymphocytes, Progenitor cell, Yolk sac, LTi, lcsh:QH301-705.5, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Yolk Sac, Hemogenic endothelium, Innate immune system, Cdh5, Innate lymphoid cell, Embryogenesis, Innate Lymphoid Cell, T-Lymphocytes, Helper-Inducer, Hematopoietic Stem Cells, Embryonic stem cell, Immunity, Innate, Cell biology, Hematopoiesis, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, ILC, lcsh:Biology (General), Liver, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030217 neurology & neurosurgery
Abstract

International audience; During embryogenesis, lymphoid tissue inducer (LTi) cells are essential for lymph node organogenesis. These cells are part of the innate lymphoid cell (ILC) family. Although their earliest embryonic hematopoietic origin is unclear, other innate immune cells have been shown to be derived from early hemogenic endothelium in the yolk sac as well as the aorta-gonad-mesonephros. A proper model to discriminate between these locations was unavailable. In this study, using a Cxcr4-CreERT2 lineage tracing model, we identify a major contribution from embryonic hemogenic endothelium, but not the yolk sac, toward LTi progenitors. Conversely, embryonic LTi cells are replaced by hematopoietic stem cell-derived cells in adults. We further show that, in the fetal liver, common lymphoid progenitors differentiate into highly dynamic alpha-lymphoid precursor cells that, at this embryonic stage, preferentially mature into LTi precursors and establish their functional LTi cell identity only after reaching the periphery.

Published
2019

22. Maintenance of Type 2 Response by CXCR6-Deficient ILC2 in Papain-Induced Lung Inflammation

Author

Ana Cumano, Rachel Golub, Sylvestre Chea, Sylvain Meunier, Thibaut Perchet, Damien Garrido, Maxime Petit, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), This research was funded by Institut Pasteur, INSERM, Ministère de la Recherche, Université Paris Diderot, ANR. Association pour la Recherche sur le Cancer to S.C. and R.G., and the Agence Nationale de la Recherche ANR (Grant 'Myeloten') to R.G, and the Institut National du Cancer (Grant « Role of the immune microenvironment during liver carcinogenesis ») to R.G, and the Agence Nationale de la Recherche ANR (Grant 8-CE15-0024-01) to S.M. and R.G., ANR-13-ISV1-0003,MYELOTEN,DEREGULATION DE L'HEMATOPOIESE PAR LA SUREXPRESSION DE L'INTERLEUKINE-10 : IMPLICATIONS DANS LE DEVELOPPEMENT DE PATHOLOGIES HEMATOLOGIQUES(2013), ANR-18-CE15-0024,NASHILCCD8,Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome.(2018), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-18-CE15-0024,NASHILCCD8,CONTRIBUTION OF ILC AND CD8 TO NON-ALCOHOLIC STEATOHEPATITIS AND PROGRESSION TOWARDS HEPATOCARCINOMA(2018)

Subjects
0301 basic medicine, Lung inflammation, Cell, Immunology, Inflammation, Biology, Article, Catalysis, lcsh:Chemistry, Inorganic Chemistry, Interferon-gamma, Mice, 03 medical and health sciences, Chemokine receptor, 0302 clinical medicine, Immune system, Papain, medicine, Animals, Eosinophilia, ILC immunity, Physical and Theoretical Chemistry, lcsh:QH301-705.5, Molecular Biology, Cells, Cultured, Spectroscopy, Receptors, CXCR6, Lung, Organic Chemistry, Innate lymphoid cell, Cancer, Pneumonia, General Medicine, medicine.disease, Lymphocyte Subsets, CXCR6, 3. Good health, Computer Science Applications, 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), lcsh:QD1-999, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, 030215 immunology
Abstract

Innate lymphoid cells (ILC) are important players of early immune defenses in situations like lymphoid organogenesis or in case of immune response to inflammation, infection and cancer. Th1 and Th2 antagonism is crucial for the regulation of immune responses, however mechanisms are still unclear for ILC functions. ILC2 and NK cells were reported to be both involved in allergic airway diseases and were shown to be able to interplay in the regulation of the immune response. CXCR6 is a common chemokine receptor expressed by all ILC, and its deficiency affects ILC2 and ILC1/NK cell numbers and functions in lungs in both steady-state and inflammatory conditions. We determined that the absence of a specific ILC2 KLRG1+ST2&ndash, subset in CXCR6-deficient mice is probably dependent on CXCR6 for its recruitment to the lung under inflammation. We show that despite their decreased numbers, lung CXCR6-deficient ILC2 are even more activated cells producing large amount of type 2 cytokines that could drive eosinophilia. This is strongly associated to the decrease of the lung Th1 response in CXCR6-deficient mice.

Published
2019

23. A wave of embryonic bipotent T/lymphoid tissue inducer progenitors regulates the maturation of medullary thymic epithelial cells

Author

Paulo Vieira, Ramy Elsaid, Rachel Golub, Antonio Bandeira, Laina Freyer, Lorea Iturri, Pablo Pereira, Sylvain Meunier, Odile Burlen-Defranoux, Francisca Soares-da-Silva, Thibaut Perchet, Ana Cumano, and Elisa Gomez Perdiguero

Subjects
Haematopoiesis, Lymphatic system, Lineage (genetic), medicine.anatomical_structure, Immune system, medicine, Hematopoietic stem cell, Biology, Progenitor cell, Yolk sac, Embryonic stem cell, Cell biology
Abstract

SUMMARYMultiple waves of hematopoietic progenitors with distinct lineage potentials are differentially regulated in time and space. We show that the first thymic seeding progenitors comprise a unique population of bipotent cells that generate lymphoid tissue inducer and invariant Vγ5+ T cells. Both populations are of embryonic origin and induce the maturation of medullary thymic epithelial cells. Indeed, temporal depletion of the first wave of thymocytes results in a five-fold reduction of mature medullary thymic epithelial cells, after birth. We further show that these progenitors are of hematopoietic stem cell, and not, of yolk sac origin, despite the temporal overlap between the onset of lymphopoiesis and the transient expression of lymphoid transcripts in yolk sac precursors, that does not impact their strict erythro-myeloid potential. Our work highlights the relevance of the developmental timing on the emergence of different lymphoid subsets required for the establishment of a functionally diverse immune system.

Published
2019

24. Asynchronous lineage priming determines commitment to T cell and B cell lineages in fetal liver

Author

Ana Cumano, Rachel Golub, Paulo Vieira, Guillaume Soubigou, Pablo Pereira, Claire Berthault, Sylvestre Chea, Odile Burlen-Defranoux, Cyrille Ramond, Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Transcriptome et Epigénome (PF2), Institut Pasteur [Paris] (IP), Supported by the Pasteur Institute, Institut National de la Santé et de la Recherche Médicale (INSERM), the Ministère de la Recherche (C.B., C.R. and S.C.), Association pour la Recherche sur le Cancer (S.C. and R.G.), La Ligue Contre Le Cancer (C.B. and C.R.), Université Paris Diderot (C.B., R.G. and S.C.), Université Pierre et Marie Curie (C.R.), the Agence Nationale de la Recherche (project Myeloten (R.G.), program REVIVE (Investment for the Future) (A.C.), and project Twothyme (A.C.) and the Pasteur-Weizmann Foundation (A.C.), We thank A. Bandeira and D. Guy-Grand for critical reading, S. Novault and S. Schmutz for support, H.-R. Rodewald (German Cancer Center DKFZ) for the IL-7Rα-Cre mouse line, and P. Chambon (IGBMC Strasbourg) for the TSLP-KO mice. This work benefited from data assembled by the ImmGen Consortium, ANR-13-ISV1-0003,MYELOTEN,DEREGULATION DE L'HEMATOPOIESE PAR LA SUREXPRESSION DE L'INTERLEUKINE-10 : IMPLICATIONS DANS LE DEVELOPPEMENT DE PATHOLOGIES HEMATOLOGIQUES(2013), ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-14-CE11-0022,Twothyme,Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T.(2014), PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], and ANR-10-LABX-0073/10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010)

Subjects
0301 basic medicine, Molecular biology, T-Lymphocytes, T cell, Immunology, Cell, Priming (immunology), Mice, Transgenic, Biology, Immunophenotyping, Mice, 03 medical and health sciences, Fetus, Precursor cell, medicine, Animals, Cluster Analysis, Immunology and Allergy, Cell Lineage, Lymphopoiesis, Progenitor cell, B cell, B-Lymphocytes, Gene Expression Profiling, Interleukin-7, Gene Expression Regulation, Developmental, Cell Differentiation, Lymphoid Progenitor Cells, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Liver, T cell differentiation, [SDV.IMM]Life Sciences [q-bio]/Immunology, Transcriptome, Biomarkers, Signal Transduction
Abstract

International audience; The molecular events that initiate lymphoid-lineage specification remain unidentified because the stages of differentiation during which lineage commitment occurs are difficult to characterize. We isolated fetal liver progenitor cells undergoing restriction of their differentiation potential toward the T cell-innate lymphoid cell lineage or the B cell lineage. Transcripts that defined the molecular signatures of these two subsets were sequentially upregulated in lympho-myeloid precursor cells and in common lymphoid progenitor cells, respectively, and this preceded lineage restriction; this indicates that T cell-versus-B cell commitment is not a binary fate 'decision'. The T cell-bias and B cell-bias transcriptional programs were frequently co-expressed in common lymphoid progenitor cells and were segregated in subsets biased toward T cell differentiation or B cell differentiation, after interleukin 7 (IL-7) signaling that controlled the number of progenitor cells engaging in T cell differentiation versus B cell differentiation.

Published
2017

25. The Heterogeneity of Ly6Chi Monocytes Controls Their Differentiation into iNOS+ Macrophages or Monocyte-Derived Dendritic Cells

Author

Ana-Maria Lennon-Duménil, Enrique Gutiérrez-Martinez, Stéphanie Hugues, Grégoire Lauvau, Hannah Garner, Jakob Loschko, Emmanuel L. Gautier, Rachel Golub, Jake Y. Henry, Elisa Gomez-Perdiguero, Shinelle Menezes, Frederic Geissmann, M. Paula Longhi, Daisy Melandri, Christian E. Jacome-Galarza, Alain Bessis, Pierre Guermonprez, Thibaut Perchet, Giorgio Anselmi, Juan Dubrot, Sergio A. Quezada, Rajen Patel, Michel C. Nussenzweig, Centre for Cellular and Molecular Biology of Inflammation, King‘s College London, Peter Gorer Department of Immunobiology, laboratory of phagocyte immunobiology, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Rockefeller University [New York], University of Geneva [Switzerland], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Barts and the London Medical School, University College of London [London] (UCL), Albert Einstein College of Medicine [New York], Institut Curie [Paris], École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL), Memorial Sloane Kettering Cancer Center [New York], The research was supported by the MRC (MR/K01241X/1), BBSRC (BB/M0297351) and King’s Health partners., Rockefeller University, CHU Pitié-Salpêtrière [APHP], Albert Einstein College of Medicine, Institut Curie, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Genève = University of Geneva (UNIGE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and École normale supérieure - Paris (ENS-PSL)

Subjects
Nitric Oxide Synthase Type II/immunology, 0301 basic medicine, Adoptive cell transfer, Ly/immunology, [SDV]Life Sciences [q-bio], Cellular differentiation, Nitric Oxide Synthase Type II, Stimulation, Cell Separation, ddc:616.07, Polymerase Chain Reaction, Cell Differentiation/immunology, Mice, 0302 clinical medicine, Antigens, Ly, Immunology and Allergy, Oligonucleotide Array Sequence Analysis, medicine.diagnostic_test, Cell Differentiation, Flow Cytometry, Adoptive Transfer, macrophages, Cell biology, Infectious Diseases, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, monocytes, Intracellular, Macrophages/cytology/immunology, monocyte-derived dendritic cells, Immunology, Inflammation, Biology, Dendritic Cells/cytology/immunology, Article, Flow cytometry, PU.1 transcription factor, 03 medical and health sciences, TheoryofComputation_ANALYSISOFALGORITHMSANDPROBLEMCOMPLEXITY, medicine, Animals, Antigens, Monocytes/cytology/immunology, Progenitor, Monocyte, GM-CSF, Dendritic Cells, 030104 developmental biology, 030215 immunology
Abstract

Summary Inflammation triggers the differentiation of Ly6Chi monocytes into microbicidal macrophages or monocyte-derived dendritic cells (moDCs). Yet, it is unclear whether environmental inflammatory cues control the polarization of monocytes toward each of these fates or whether specialized monocyte progenitor subsets exist before inflammation. Here, we have shown that naive monocytes are phenotypically heterogeneous and contain an NR4A1- and Flt3L-independent, CCR2-dependent, Flt3+CD11c−MHCII+PU.1hi subset. This subset acted as a precursor for FcγRIII+PD-L2+CD209a+, GM-CSF-dependent moDCs but was distal from the DC lineage, as shown by fate-mapping experiments using Zbtb46. By contrast, Flt3−CD11c−MHCII−PU.1lo monocytes differentiated into FcγRIII+PD-L2−CD209a−iNOS+ macrophages upon microbial stimulation. Importantly, Sfpi1 haploinsufficiency genetically distinguished the precursor activities of monocytes toward moDCs or microbicidal macrophages. Indeed, Sfpi1+/− mice had reduced Flt3+CD11c−MHCII+ monocytes and GM-CSF-dependent FcγRIII+PD-L2+CD209a+ moDCs but generated iNOS+ macrophages more efficiently. Therefore, intercellular disparities of PU.1 expression within naive monocytes segregate progenitor activity for inflammatory iNOS+ macrophages or moDCs., Graphical Abstract, Highlights • Murine Ly6ChiCD115+ monocytes are heterogeneous • DC-related genes (Cd209a and MHCII) are expressed in a subset of FcγRIII+ monocytes • GM-CSF-dependent CD209a+ moDCs are generated by FcγRIII+CD209a+MHCII+ monocytes • iNOS+ macrophages are generated by FcγRIII+CD209a−MHCII− monocytes, Monocytes can differentiate into multiple progenies during inflammation. Here, Menezes et al. show that monocytes from naive mice are heterogeneous and contain distinct precursor subsets giving rise to iNOS+ inflammatory macrophages or GM-CSF-induced CD209a+ monocyte-derived dendritic cells.

Published
2016

26. CCR10 + ILC2s with ILC1-like properties exhibit a protective function in severe allergic asthma

Author

Vincent Lombardi, Rachel Golub, Sylvie Chollet-Martin, C. Neukirch, Chloé Beuraud, Emmanuel Nony, Sonia Luce, Sabi Airouche, Thibaut Perchet, Véronique Baron-Bodo, Philippe Moingeon, Michel Aubier, Laurent Mascarell, Emmanuel Naline, S. Horiot, Philippe Devillier, Stallergenes SA (Stallergenes), Stallergenes, Hôpital Foch [Suresnes], Université Paris-Saclay, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Institut National de la Santé et de la Recherche Médicale (INSERM), Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11), and Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, medicine.diagnostic_test, business.industry, Immunology, medicine.disease, Pathophysiology, 3. Good health, Flow cytometry, Allergic inflammation, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030228 respiratory system, Amphiregulin, Downregulation and upregulation, Immunology and Allergy, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, CCL27, CCR10, business, Asthma
Abstract

International audience; We previously showed that patients with severe allergic asthma have high numbers of circulating ILC2s expressing CCR10.METHOD:Herein, CCR10+ ILC2s were further analyzed in the blood of healthy individuals or patients with allergic and non-allergic asthma. Characteristics of human CCR10+ and CCR10- ILC2s were assessed by flow cytometry as well as single-cell multiplex RT-qPCR. The role of CCR10+ ILC2s in asthma pathophysiology was studied in allergen-treated mice.RESULTS:When compared to healthy controls, CCR10+ ILC2s are enriched in the blood of both allergic and non-allergic severe asthmatic patients, and these cells are recruited to the lungs. Plasma concentrations of the CCR10 ligand CCL27 are significantly increased in severe asthmatics when compared to non-asthmatic patients. CCR10+ ILC2s secrete little TH 2 cytokines, but exhibit ILC1-like properties, including a capacity to produce IFN-γ. Also, single-cell analysis reveals that the CCR10+ ILC2 subset is enriched in cells expressing amphiregulin. CCR10+ ILC2 depletion, as well as blocking of IFN-γ activity, exacerbates airway hyperreactivity in allergen-challenged mice, providing evidence for a protective role of these cells in allergic inflammation.CONCLUSIONS:Frequencies of circulating CCR10+ ILC2s and CCL27 plasma concentrations represent candidate markers of asthma severity. The characterization of CCR10+ ILC2s in human samples and in mouse asthma models suggests that these cells downregulate allergic inflammation through IFN-γ production.

Published
2019

27. Natural Killer Cells and Type 1 Innate Lymphoid Cells Are New Actors in Non-alcoholic Fatty Liver Disease

Author

Rachel Golub, Philippe Gual, Elodie Vieira, Carmelo Luci, Thibaut Perchet, Vougny, Marie-Christine, INTERACTION ENTRE ALCOOL ET L'OBÉSITÉ DANS LA SÉVÉRITÉ DES MALADIES DU FOIE GRAS. - - HEPAMETOL2015 - ANR-15-CE14-0016 - AAPG2015 - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Etude de la signalisation SYK dans les maladies inflammatoires chroniques - - INFLAMMASYK2018 - ANR-18-CE14-0019 - AAPG2018 - VALID, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome. - - NASHILCCD82018 - ANR-18-CE15-0024 - AAPG2018 - VALID, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work is supported by grants from Institut National de la santé et de la recherche Médicale (INSERM), Université Côte d'Azur and charities (Association Française pour l'Etude du Foie (AFEF)/LFB to PG). This work was also funded by the French Government (National Research Agency, ANR): #ANR-15-CE14-0016-01, #ANR-18-CE14-0019-02 and through the Investments for the Future LABEX SIGNALIFE (#ANR-11-LABX-0028-01) and the UCAJEDI Investments in the Future project (#ANR-15-IDEX-01). This work was supported by the Fondation pour la Recherche Médicale, grant number ECO20170637473 to EV, TP, and RG work is supported by Institut Pasteur, Institut National de la Santé et de la Recherche Médicale, Université Paris Diderot, and ANR project NASHILCCD8 (#18-CE15-0024-01)., ANR-15-CE14-0016,HEPAMETOL,INTERACTION ENTRE ALCOOL ET L'OBÉSITÉ DANS LA SÉVÉRITÉ DES MALADIES DU FOIE GRAS.(2015), ANR-18-CE14-0019,INFLAMMASYK,Etude de la signalisation SYK dans les maladies inflammatoires chroniques(2018), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), ANR-18-CE15-0024,NASHILCCD8,Contribution des ILC et des cellules T CD8 à la stéatose hépatique non alcoolique et à sa progression vers l'hépatocarcinome.(2018), Université Nice Sophia Antipolis (... - 2019) (UNS), and Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, [SDV.IMM] Life Sciences [q-bio]/Immunology, Mini Review, Population, Immunology, Inflammation, NK cells, Biology, liver, ILC1, 03 medical and health sciences, 0302 clinical medicine, Immune system, Non-alcoholic Fatty Liver Disease, NAFLD, medicine, Immunology and Allergy, Animals, Humans, Lymphocytes, education, Liver injury, education.field_of_study, Fatty liver, Innate lymphoid cell, NASH, medicine.disease, Immunity, Innate, 3. Good health, Gastrointestinal Tract, Killer Cells, Natural, 030104 developmental biology, medicine.anatomical_structure, Adipose Tissue, inflammation, Hepatocyte, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, Steatohepatitis, Energy Metabolism, lcsh:RC581-607, Biomarkers, 030215 immunology
Abstract

International audience; Obesity and associated liver diseases (Non Alcoholic Fatty Liver Disease, NAFLD) are a major public health problem with increasing incidence in Western countries (25% of the affected population). These complications develop from a fatty liver (steatosis) to an inflammatory state (steatohepatitis) evolving toward fibrosis and hepatocellular carcinoma. Lipid accumulation in the liver contributes to hepatocyte cell death and promotes liver injury. Local immune cells are activated either by Danger Associated Molecular Patterns (DAMPS) released by dead hepatocytes or by bacterial products (PAMPS) reaching the liver due to increased intestinal permeability. The resulting low-grade inflammatory state promotes the progression of liver complications toward more severe grades. Innate lymphoid cells (ILC) are an heterogeneous family of five subsets including circulating Natural Killer (NK) cells, ILC1, ILC2, ILC3, and lymphocytes tissue-inducer cells (LTi). NK cells and tissue-resident ILCs, mainly located at epithelial surfaces, are prompt to rapidly react to environmental changes to mount appropriate immune responses. Recent works have demonstrated the interplay between ILCs subsets and the environment within metabolic active organs such as liver, adipose tissue and gut during diet-induced obesity leading or not to hepatic abnormalities. Here, we provide an overview of the newly roles of NK cells and ILC1 in metabolism focusing on their contribution to the development of NAFLD. We also discuss recent studies that demonstrate the ability of these two subsets to influence tissue-specific metabolism and how their function and homeostasis are affected during metabolic disorders.

Published
2019

28. New Molecular Insights into Immune Cell Development

Author

Ana Cumano, Rachel Golub, Claire Berthault, Antonio Bandeira, Cyrille Ramond, Maxime Petit, Pablo Pereira, Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was financed by the Pasteur Institute, INSERM, ANR (grant Twothyme) for A.C. and (grant Myeloten) R.G. and by REVIVE Future Investment Program and Pasteur-Weizmann Foundation through grants to A.C. We apologize to all colleagues that contributed to the field and whose work could not be cited here due to limitation in space availability., We thank members of the A.C. laboratory for many fruitful discussions., ANR-14-CE11-0022,Twothyme,Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T.(2014), ANR-13-ISV1-0003,MYELOTEN,DEREGULATION DE L'HEMATOPOIESE PAR LA SUREXPRESSION DE L'INTERLEUKINE-10 : IMPLICATIONS DANS LE DEVELOPPEMENT DE PATHOLOGIES HEMATOLOGIQUES(2013), Vougny, Marie-Christine, Appel à projets générique - Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T. - - Twothyme2014 - ANR-14-CE11-0022 - Appel à projets générique - VALID, Blanc – Accords bilatéraux 2013 - DEREGULATION DE L'HEMATOPOIESE PAR LA SUREXPRESSION DE L'INTERLEUKINE-10 : IMPLICATIONS DANS LE DEVELOPPEMENT DE PATHOLOGIES HEMATOLOGIQUES - - MYELOTEN2013 - ANR-13-ISV1-0003 - Blanc – Accords bilatéraux 2013 - VALID, and Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, transcriptional signatures, [SDV.IMM] Life Sciences [q-bio]/Immunology, First line, Immunology, innate lymphoid cells, Organogenesis, lineage commitment, Thymus Gland, Biology, Lymphocyte Activation, 03 medical and health sciences, 0302 clinical medicine, Immune system, lymphoid progenitors, Paracrine Communication, Immunology and Allergy, Animals, Humans, Lymphoid progenitors, Cell Lineage, Lymphocytes, thymus-settling progenitors, B-Lymphocytes, Lineage commitment, Cell growth, Innate lymphoid cell, Cell Differentiation, Lymphoid Progenitor Cells, Immunity, Innate, Cell biology, 030104 developmental biology, Cellular Microenvironment, 030220 oncology & carcinogenesis, Cytokines, Natural Killer T-Cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Transcriptome, Lymphocyte subsets, fetal liver
Abstract

International audience; During development innate lymphoid cells and specialized lymphocyte subsets colonize peripheral tissues, where they contribute to organogenesis and later constitute the first line of protection while maintaining tissue homeostasis. A few of these subsets are produced only during embryonic development and remain in the tissues throughout life. They are generated through a unique developmental program initiated in lympho-myeloid-primed progenitors, which lose myeloid and B cell potential. They either differentiate into innate lymphoid cells or migrate to the thymus to give rise to embryonic T cell receptor-invariant T cells. At later developmental stages, adaptive T lymphocytes are derived from lympho-myeloid progenitors that colonize the thymus, while lymphoid progenitors become specialized in the production of B cells. This sequence of events highlights the requirement for stratification in the establishment of immune functions that determine efficient seeding of peripheral tissues by a limited number of cells.

Published
2019

29. Tbet promotes NK cell egress from the bone marrow and CXCR6 expression in immature NK cells

Author

Antonia O. Cuff, Rachel Golub, Simone Dertschnig, Thibaut Perchet, and Male

Subjects
0303 health sciences, Cell, Spleen, Biology, Phenotype, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Gene expression, Cancer research, medicine, Bone marrow, Lymph, 030304 developmental biology, 030215 immunology
Abstract

Tbet-deficient mice have reduced NK cells in blood and spleen, but increased NK cells in bone marrow and lymph nodes, a phenotype that is thought to be due to defective migration. Here, we revisit the role of Tbet in NK cell bone marrow egress. We definitively show that the accumulation of NK cells in the bone marrow of Tbet-deficient (Tbx21-/-) animals occurs because of a cell-intrinsic migration defect. We identify a profile of gene expression, co-ordinated by Tbet, which affects the localisation of NK cells in the bone marrow. Tbet promotes Cxcr6 expression and immature NK cells accumulate in the bone marrow of CXCR6-deficient mice. This suggests that CXCR6 is among the mediators of migration, controlled by Tbet, that co-ordinate NK cell bone marrow egress.

Published
2019

30. CXCR6 Expression Is Important for Retention and Circulation of ILC Precursors

Author

Thibaut Perchet, Sylvestre Chea, Ana Cumano, Maxime Petit, Rachel Golub, Cécilie Possot, Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), The authors thank A. Goldrath for providing Id2Yfp/+ mouse strain. This study is supported by the Ministère de la recherche (Sylvestre Chea, Thibaut Perchet), Association pour la Recherche sur le Cancer (Sylvestre Chea, Rachel Golub), Institut Pasteur (Ana Cumano), Université Paris Diderot (Rachel Golub, Sylvestre Chea, Thibaut Perchet), Institut National de la Santé et de la Recherche Médicale (Ana Cumano), Institut National du Cancer (Rachel Golub, Maxime Petit), and the Agence Nationale de Recherches (Rachel Golub)., Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Vougny, Marie-Christine

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, Article Subject, Immunology, Bone Marrow Cells, Mice, Transgenic, Flow cytometry, Mice, Bone Marrow, In vivo, lcsh:Pathology, Animals, Medicine, Lymphocytes, skin and connective tissue diseases, Cell Proliferation, Receptors, CXCR6, Receptors, CXCR, Mucous Membrane, biology, medicine.diagnostic_test, business.industry, Cell growth, CD44, Innate lymphoid cell, Cell Biology, Flow Cytometry, Embryonic stem cell, Immunity, Innate, Lymphocyte Subsets, Culture Media, Cell biology, Intestines, body regions, medicine.anatomical_structure, Gene Expression Regulation, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Bone marrow, business, lcsh:RB1-214, Research Article, Homing (hematopoietic)
Abstract

Innate lymphoid cells are present at mucosal sites and represent the first immune barrier against infections, but what contributes to their circulation and homing is still unclear. UsingRag2−/−Cxcr6Gfp/+reporter mice, we assessed the expression and role of CXCR6 in the circulation of ILC precursors and their progeny. We identify CXCR6 expressing ILC precursors in the bone marrow and characterize their significant increase in CXCR6-deficient mice at steady state, indicating their partial retention in the bone marrow after CXCR6 ablation. Circulation was also impaired during embryonic life as fetal liver from CXCR6-deficient embryos displayed decreased numbers of ILC3 precursors. When injected, fetal CXCR6-deficient ILC3 precursors also fail to home and reconstitute ILC compartmentsin vivo. We show that adult intestinal ILC subsets have heterogeneous expression pattern of CXCR6, integrinα4β7, CD62L, CD69, and CD44, with ILC1 and ILC3 being more likely tissue resident lymphocytes. Intestinal ILC subsets were unchanged in percentages and numbers in both mice. We demonstrate that the ILC frequency is maintained due to a significant increase of ILC peripheral proliferation, as well as an increased proliferation of thein situILC precursors to compensate their retention in the bone marrow.

Published
2015

31. Single-cell analysis defines the divergence between the innate lymphoid cell lineage and lymphoid tissue–inducer cell lineage

Author

Herman Gudjonson, Rachel Golub, Sylvestre Chea, Aaron R. Dinner, Michael G. Constantinides, Isabel E. Ishizuka, Albert Bendelac, Committee on Immunology, University of Chicago, Department of pathology, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, institute of biophysical dynamics, department of biochemistry, Lymphopoïèse, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Supported by the US National Institutes of Health (R01 HL118092, AI038339 and AI108643) and by the Digestive Diseases Research Center of Excellence (P30DK42086), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Effector, Cellular differentiation, Immunology, Innate lymphoid cell, Priming (immunology), Biology, Molecular biology, Gene expression profiling, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Single-cell analysis, Precursor cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunology and Allergy, Transcription factor, 030215 immunology
Abstract

International audience; The precise lineage relationship between innate lymphoid cells (ILCs) and lymphoid tissue-inducer (LTi) cells is poorly understood. Using single-cell multiplex transcriptional analysis of 100 lymphoid genes and single-cell cultures of fetal liver precursor cells, we identified the common proximal precursor to these lineages and found that its bifurcation was marked by differential induction of the transcription factors PLZF and TCF1. Acquisition of individual effector programs specific to the ILC subsets ILC1, ILC2 and ILC3 was initiated later, at the common ILC precursor stage, by transient expression of mixed ILC1, ILC2 and ILC3 transcriptional patterns, whereas, in contrast, the development of LTi cells did not go through multilineage priming. Our findings provide insight into the divergent mechanisms of the differentiation of the ILC lineage and LTi cell lineage and establish a high-resolution 'blueprint' of their development.

Published
2016

32. Osteogenic Potential of Mesenchymal Stromal Cells Contributes to Primary Myelofibrosis

Author

Lisa Pieri, Johanna Konopacki, Adrienne Anginot, Rachel Golub, Olivier Pierre-Louis, Jean-Christophe Ianotto, Alessandro M. Vannucchi, Bernadette Guerton, Nathalie Rochet, Marie-Françoise Bourgeade, Thierry de Revel, Christophe Martinaud, Brigitte Dupriez, Jean-Jacques Lataillade, Sandrine Schmutz, Patricia Albanese, Christophe Desterke, Jean-Baptiste Souraud, Emilie Henault, Frédéric Torossian, Marie-Caroline Le Bousse-Kerdilès, Interactions cellules souches-niches : physiologie, tumeurs et réparation tissulaire, Université Paris-Sud - Paris 11 (UP11)-Service de Santé des Armées-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), SFR89, University Paris-Sud, Département de biologie clinique, Hôpital d'instruction des Armées Percy, Service de Santé des Armées-Service de Santé des Armées, FIM, French Intergroup on Myeloproliferative neoplasmss, Département d'hématologie, MPN-CRIMM, Azienda Ospedaliera-Universitaria, Université Paris Diderot - Paris 7 (UPD7), Lymphopoïèse, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), EAC 7149, Etablissement Français du Sang (EFS), EFS, Centre Hospitalier de Lens, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hépato-biliaire (CHB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Studies in Florence were supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC, Milan, Italy), Special Program Molecular Clinical Oncology 5×1000 to AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM) project #1005 (A.M. Vannucchi)., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (... - 2019) (UNS), and Institut de Recherche Biomédicale des Armées (IRBA)

Subjects
Adult, Male, Cancer Research, Pathology, medicine.medical_specialty, Stromal cell, Cellular differentiation, Mice, Nude, Biology, Polymerase Chain Reaction, Mice, medicine, Animals, Humans, Myelofibrosis, Cells, Cultured, Myeloproliferative neoplasm, Aged, Aged, 80 and over, Ossification, Heterotopic, Mesenchymal stem cell, Cell Differentiation, Mesenchymal Stem Cells, Middle Aged, medicine.disease, 3. Good health, Extramedullary hematopoiesis, Haematopoiesis, medicine.anatomical_structure, Oncology, Primary Myelofibrosis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Heterografts, Female, Bone marrow
Abstract

Primary myelofibrosis is a myeloproliferative neoplasm that is a precursor to myeloid leukemia. Dysmegakaryopoiesis and extramedullary hematopoiesis characterize primary myelofibrosis, which is also associated with bone marrow stromal alterations marked by fibrosis, neoangiogenesis, and osteomyelosclerosis. In particular, contributions to primary myelofibrosis from mesenchymal stromal cells (MSC) have been suggested by mouse studies, but evidence in humans remains lacking. In this study, we show that bone marrow MSCs from primary myelofibrosis patients exhibit unique molecular and functional abnormalities distinct from other myeloproliferative neoplasms and these abnormalities are maintained stably ex vivo in the absence of leukemic cells. Primary myelofibrosis-MSC overexpressed heparin-binding cytokines, including proinflammatory TGFβ1 and osteogenic BMP-2, as well as glycosaminoglycans such as heparan sulfate and chondroitin sulfate. Transcriptome and functional analyses revealed alterations in MSC differentiation characterized by an increased osteogenic potential and a TGFβ1 signaling signature. Accordingly, phospho-Smad2 levels were intrinsically increased in primary myelofibrosis-MSC along with enhanced expression of the master bone regulator RUNX2, while inhibition of the endogenous TGFβ1 receptor TGFβR1 impaired osteogenic differentiation in these MSCs. Taken together, our results define the source of a critical osteogenic function in primary myelofibrosis that supports its pathophysiology, suggesting that combined targeting of both the hematopoietic and stromal cell compartments in primary myelofibrosis patients may heighten therapeutic efficacy. Cancer Res; 75(22); 4753–65. ©2015 AACR.

Published
2015

33. An Id2

Author

Wei, Xu, Dylan E, Cherrier, Sylvestre, Chea, Christian, Vosshenrich, Nicolas, Serafini, Maxime, Petit, Pentao, Liu, Rachel, Golub, and James P, Di Santo

Subjects
Transcription, Genetic, Lymphopoiesis, Models, Immunological, GATA3 Transcription Factor, T-Lymphocytes, Helper-Inducer, Hematopoietic Stem Cells, Adoptive Transfer, Immunity, Innate, Article, Killer Cells, Natural, Mice, Inbred C57BL, Luminescent Proteins, Mice, Gene Expression Regulation, Genes, Reporter, Animals, Cell Lineage, Promyelocytic Leukemia Zinc Finger Protein, Single-Cell Analysis, Inhibitor of Differentiation Protein 2
Abstract

Innate lymphoid cell (ILC) development proposes that ILC precursors (ILCPs) segregate along natural killer (NK) cell versus helper cell (ILC1, ILC2, ILC3) pathways, the latter depending on expression of Id2, Zbtb16, and Gata3. We have developed an Id2-reporter strain expressing red fluorescent protein (RFP) in the context of normal Id2 expression to re-examine ILCP phenotype and function. We show that bone-marrow ILCPs were heterogeneous and harbored extensive NK-cell potential in vivo and in vitro. By multiplexing Id2(RFP) with Zbtb16(CreGFP) and Bcl11b(tdTomato) strains, we made a single-cell dissection of the ILCP compartment. In contrast with the current model, we have demonstrated that Id2(+)Zbtb16(+) ILCPs included multi-potent ILCPs that retained NK-cell potential. Late-stage ILC2P and ILC3P compartments could be defined by differential Zbtb16 and Bcl11b expression. We suggest a revised model for ILC differentiation that redefines the cell-fate potential of helper-ILC-restricted Zbtb16(+) ILCPs.

Published
2018

34. CCR10

Author

Chloé, Beuraud, Vincent, Lombardi, Sonia, Luce, Stéphane, Horiot, Emmanuel, Naline, Catherine, Neukirch, Sabi, Airouche, Thibaut, Perchet, Rachel, Golub, Philippe, Devillier, Sylvie, Chollet-Martin, Véronique, Baron-Bodo, Emmanuel, Nony, Michel, Aubier, Laurent, Mascarell, and Philippe, Moingeon

Subjects
Receptors, CCR10, Allergens, Severity of Illness Index, Asthma, Immunity, Innate, Lymphocyte Subsets, Disease Models, Animal, Interferon-gamma, Mice, Animals, Cytokines, Humans, Disease Susceptibility, Lymphocyte Count, Biomarkers
Abstract

We previously showed that patients with severe allergic asthma have high numbers of circulating ILC2s expressing CCR10.Herein, CCR10When compared to healthy controls, CCR10Frequencies of circulating CCR10

Published
2018

35. Origin and Immunological Functions of Spleen Stromal Cells

Author

Andrea Brendolan, Jonathan K. H. Tan, Takeshi Watanabe, Rachel Golub, Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bond University [Gold Coast], Kyoto University, IRCCS San Raffaele Scientific Institute [Milan, Italie], This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancero (AIRC) Special Program Molecular Clinical Oncology, 5 per mille #9965, AIRC Investigator Grant #19867, and by the Italian Ministry of Health, Ricerca Finalizzata RF-2011-02347691 to A.B. Also by grants from the Institut Pasteur, INSERM, Université Paris Diderot, Association pour la Recherche sur le Cancer, and ANR grant ‘Myeloten’ the Institut National du Cancer (Role of the immune microenvironment during liver carcinogenesis) to R.G. Also, grants from the National Health and Medical Research Council of Australia (#1078247) to J.T., and from the Ministry of Education, Culture, Sports, Science and Technology, Japan to T.W., ANR-13-ISV1-0003,MYELOTEN,DEREGULATION DE L'HEMATOPOIESE PAR LA SUREXPRESSION DE L'INTERLEUKINE-10 : IMPLICATIONS DANS LE DEVELOPPEMENT DE PATHOLOGIES HEMATOLOGIQUES(2013), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Kyoto University [Kyoto], Vougny, Marie-Christine, and Blanc – Accords bilatéraux 2013 - DEREGULATION DE L'HEMATOPOIESE PAR LA SUREXPRESSION DE L'INTERLEUKINE-10 : IMPLICATIONS DANS LE DEVELOPPEMENT DE PATHOLOGIES HEMATOLOGIQUES - - MYELOTEN2013 - ANR-13-ISV1-0003 - Blanc – Accords bilatéraux 2013 - VALID

Subjects
0301 basic medicine, Stromal cell, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Spleen, Biology, Adaptive Immunity, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, medicine, Immunology and Allergy, Animals, Humans, Lymphocytes, Immunodeficiency, medicine.disease, Acquired immune system, 3. Good health, Extramedullary hematopoiesis, 030104 developmental biology, medicine.anatomical_structure, Lymphatic system, Hematopoiesis, Extramedullary, [SDV.IMM]Life Sciences [q-bio]/Immunology, Signal transduction, Stromal Cells, 030215 immunology, Signal Transduction
Abstract

International audience; The mammalian spleen is a peripheral lymphoid organ that plays a central role in host defense. Consequently, the lack of spleen is often associated with immunodeficiency and increased risk of overwhelming infections. Growing evidence suggests that non-hematopoietic stromal cells are central players in spleen development, organization, and immune functions. In addition to its immunological role, the spleen also provides a site for extramedullary hematopoiesis (EMH) in response to injuries. A deeper understanding of the biology of stromal cells is therefore essential to fully comprehend how these cells modulate the immune system during normal and pathological conditions. Here, we review the specificities of the different mouse spleen stromal cell subsets and complement the murine studies with human data when available.

Published
2018

36. Single-cell Gene Expression Using Multiplex RT-qPCR to Characterize Heterogeneity of Rare Lymphoid Populations

Author

Thibaut Perchet, Sylvestre Chea, Milena Hasan, Ana Cumano, Rachel Golub, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Centre d'Immunologie Humaine (CIH), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the Institut Pasteur, INSERM, Université Paris Diderot and by the Ministère de la Recherche (to S.C.), the Association pour la Recherche sur le Cancer (to S.C. and R.G.), the REVIVE Future Investment Program and the Agence Nationale de Recherche (ANR, grant 'Twothyme' to A.C.), ANR grant 'Myeloten' (to R.G.), and the Institut National du Cancer (Role of the immune microenvironment during liver carcinogenesis, to R.G.)., ANR-14-CE11-0022,Twothyme,Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T.(2014), ANR-13-ISV1-0003,MYELOTEN,DEREGULATION DE L'HEMATOPOIESE PAR LA SUREXPRESSION DE L'INTERLEUKINE-10 : IMPLICATIONS DANS LE DEVELOPPEMENT DE PATHOLOGIES HEMATOLOGIQUES(2013), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7)

Subjects
0301 basic medicine, General Chemical Engineering, Cellular differentiation, Population, Biology, Real-Time Polymerase Chain Reaction, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Single-cell analysis, Gene expression, Genetics, Humans, Multiplex, Lymphocytes, education, Gene, education.field_of_study, General Immunology and Microbiology, General Neuroscience, Gene Expression Profiling, Cell Differentiation, Gene signature, 030104 developmental biology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Single-Cell Analysis, Cell activation
Abstract

International audience; Gene expression heterogeneity is an interesting feature to investigate in lymphoid populations. Gene expression in these cells varies during cell activation, stress, or stimulation. Single-cell multiplex gene expression enables the simultaneous assessment of tens of genes(1)(,)(2)(,)(3). At the single-cell level, multiplex gene expression determines population heterogeneity(4)(,)(5). It allows for the distinction of population heterogeneity by determining both the probable mix of diverse precursor stages among mature cells and also the diversity of cell responses to stimuli. Innate lymphoid cells (ILC) have been recently described as a population of innate effectors of the immune response(6)(,)(7). In this protocol, cell heterogeneity of the ILC hepatic compartment is investigated during homeostasis. Currently, the most widely used technique to assess gene expression is RT-qPCR. This method measures gene expression only one gene at a time. Additionally, this method cannot estimate heterogeneity of gene expression, since multiple cells are needed for one test. This leads to the measurement of the average gene expression of the population. When assessing large numbers of genes, RT-qPCR becomes a time-, reagent-, and sample-consuming method. Hence, the trade-offs limit the number of genes or cell populations that can be evaluated, increasing the risk of missing the global picture. This manuscript describes how single-cell multiplex RT-qPCR can be used to overcome these limitations. This technique has benefited from recent microfluidics technological advances(1)(,)(2). Reactions occurring in multiplex RT-qPCR chips do not exceed the nanoliter-level. Hence, single-cell gene expression, as well as simultaneous multiple gene expression, can be performed in a reagent-, sample-, and cost-effective manner. It is possible to test cell gene signature heterogeneity at the clonal level between cell subsets within a population at different developmental stages or under different conditions(4)(,)(5). Working on rare populations with large numbers of conditions at the single-cell level is no longer a restriction.

Published
2017

37. Corrigendum: Evidence of innate lymphoid cell redundancy in humans

Author

Frédéric, Vély, Vincent, Barlogis, Blandine, Vallentin, Bénédicte, Neven, Christelle, Piperoglou, Thibaut, Perchet, Maxime, Petit, Nadia, Yessaad, Fabien, Touzot, Julie, Bruneau, Nizar, Mahlaoui, Nicolas, Zucchini, Catherine, Farnarier, Gérard, Michel, Despina, Moshous, Stéphane, Blanche, Arnaud, Dujardin, Hergen, Spits, Jörg H W, Distler, Andreas, Ramming, Capucine, Picard, Rachel, Golub, Alain, Fischer, and Eric, Vivier

Subjects
body regions, skin and connective tissue diseases, Article
Abstract

Innate lymphoid cells (ILCs) have potent immune functions in experimental conditions in mice, but their contribution to immunity in natural conditions in humans remains unclear. We investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in SCID patients carrying mutations of IL2RG or JAK3. T cell reconstitution was observed in SCID patients upon hematopoietic stem cell transplantation (HSCT), but the patients still exhibited drastic reduction of ILCs in the absence of myeloablation, at the exception of rare cases of ILC1 reconstitution. Remarkably, the observed ILC deficiencies were not associated with any particular susceptibility to disease, with a follow-up extending from 7 to 39 years after HSCT. We thus report here the first cases of selective ILC deficiency in humans, and show that ILCs may be dispensable in natural conditions, if T cells are present and B cell function is preserved.

Published
2016

38. Evidence of innate lymphoid cell redundancy in humans

Author

Frédéric Vély, Despina Moshous, Julie Bruneau, Catherine Farnarier, Andreas Ramming, Jörg H W Distler, Blandine Vallentin, Stéphane Blanche, Nicolas Zucchini, Mikael Ebbo, Rachel Golub, Capucine Picard, Alain Fischer, Nadia Yessaad, Maxime Petit, Fabien Touzot, Gérard Michel, Nizar Mahlaoui, Bénédicte Neven, Thibaut Perchet, Arnaud Dujardin, Vincent Barlogis, Christelle Piperoglou, Eric Vivier, Hergen Spits, Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION )-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Mi-mAbs (C/O CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), CHU Necker - Enfants Malades [AP-HP], BD Biosciences, Innate Pharma, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Department of Internal Medicine and Institute for Clinical Immunology, Friedrich Alexander University [Erlangen-Nürnberg], Collège de France (CdF), We thank all patients and their families for participating in the study, C. Bonnafous and N. Anceriz (Innate-Pharma) for monoclonal antibody to NKp46, F. Suarez (Paris), N. Schleinitz (Marseille) and Y. Bertrand (Lyon) for enrolling patients in the study, and the Laboratory of Hematology (P.E. Morange, Marseille) for sample storage. Supported by the European Research Council (THINK Advanced Grant for the E.V. laboratory), the Ligue Nationale contre le Cancer (Equipe Labellisée, E.V. laboratory), institutional grants from INSERM, CNRS and Aix-Marseille University to CIML (E.V. laboratory), the Institut Universitaire de France (E.V.), the European Research Council (Pidimmune Advanced Grant for the A.F. laboratory), institutional grants from INSERM, Paris Descartes University and Collège de France (A.F. laboratory), Investissements d’Avenir Instituts Hospitaliers Universitaires (A.F. laboratory), institutional grants from Institut Pasteur, INSERM, Université Paris Diderot and the Agence Nationale de la Recherche ('Myeloten', R.G. group), the Institut National du Cancer (R.G. group) and Université Sorbonne Paris Cité ('Mucocell', R.G. group), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Cell Biology and Histology, Experimental Immunology, Chaire Médecine expérimentale (A. Fischer), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Centre de Référence Déficits Immunitaires Héréditaires ( CEREDIH ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Lymphopoïèse, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité, Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Innate-Pharma, Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ), and Collège de France ( CdF )

Subjects
0301 basic medicine, T cell, medicine.medical_treatment, Immunology, Hematopoietic stem cell transplantation, Biology, 03 medical and health sciences, 0302 clinical medicine, Immunity, medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, skin and connective tissue diseases, B cell, Severe combined immunodeficiency, Innate lymphoid cell, medicine.disease, 3. Good health, body regions, 030104 developmental biology, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokine receptor, Tyrosine kinase, 030215 immunology
Abstract

International audience; Innate lymphoid cells (ILCs) have potent immunological functions in experimental conditions in mice, but their contributions to immunity in natural conditions in humans have remained unclear. We investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in patients with SCID who had mutation of the gene encoding the common γ-chain cytokine receptor subunit IL-2Rγ or the gene encoding the tyrosine kinase JAK3. T cell reconstitution was observed in patients with SCID after hematopoietic stem cell transplantation (HSCT), but the patients still had considerably fewer ILCs in the absence of myeloablation than did healthy control subjects, with the exception of rare cases of reconstitution of the ILC1 subset of ILCs. Notably, the ILC deficiencies observed were not associated with any particular susceptibility to disease, with follow-up extending from 7 years to 39 years after HSCT. We thus report here selective ILC deficiency in humans and show that ILCs might be dispensable in natural conditions, if T cells are present and B cell function is preserved.

Published
2016

39. Abstract A172: Cxcr6-deficiency impairs cancer vaccine efficacy and resident memory CD8+ T-cells recruitment in tumor

Author

Rachel Golub, Marie Anson, Soumaya Karaki, Eric Tartour, Thi Thuy Hien Tran, Isabelle Galy-Fauroux, and Charlotte Blanc

Subjects
Cancer Research, business.industry, medicine.medical_treatment, Immunology, Vaccine efficacy, Vaccination, Chemokine receptor, Cancer immunotherapy, medicine, Cancer research, Cytotoxic T cell, Cancer vaccine, business, CD8, Tumor Graft
Abstract

Immunization route is directly correlated with cancer vaccine efficacy. Our team previously showed that mucosal (intranasal, i.n.) and systemic (intramuscular) vaccinations are both able to induce systemic specific CD8+ T-cells but only i.n. immunization allows an efficient control of mucosal tumor growth. Indeed, the i.n. vaccination favors the tumor infiltration of specific CD8+ T-cells and especially tissue-resident memory T-cells (Trm), which are crucial for a potent antitumor activity. Based on a transcriptomic analysis, we have identified a chemokine receptor, CXCR6, highly expressed by these specific Trm CD8+ T-cells, induced by the i.n. vaccination. To understand the role of CXCR6 in vaccination efficacy, we have set up a body of experiments using heterozygous Cxcr6gfp/+ mice, where GFP reflects CXCR6 expression and homozygous Cxcr6-deficient mice Cxcr6gfp/gfp.We have then confirmed CXCR6 expression on specific Trm CD8+ T-cells induced by i.n. vaccination in lung mucosa. Using an orthotopic head and neck tumor model, CXCR6 expression on tumor-infiltrating Trm induced by i.n. immunization has also been reported. In addition, we showed that Cxcr6-deficiency impairs mice survival in a prophylactic and therapeutic i.n. vaccination settings in various mucosal tumor models. In this Cxcr6-deficient mouse model, the loss of vaccine-induced protection against tumor graft correlates with a clear reduction of Trm infiltration in tumor. Finally, in a cohort of human lung cancer, we have observed endogenous CXCR6+ Trm infiltrating these tumors in situ. To conclude, we have identified CXCR6 as a required parameter to recruit the crucial anti-tumor Trm in mucosal tumor. Our results finally indicate that CXCR6 might be a new surrogate biomarker to evaluate antitumor vaccine efficacy. Citation Format: Soumaya Karaki, Charlotte Blanc, Thi Tran, Isabelle Galy-Fauroux, Marie Anson, Rachel Golub, Eric Tartour. Cxcr6-deficiency impairs cancer vaccine efficacy and resident memory CD8+ T-cells recruitment in tumor [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A172.

Published
2019

40. HLA-Fatal attraction

Author

Frédéric Vély, Eric Vivier, Rachel Golub, Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION )-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Receptors, KIR3DS1, Lymphokine-activated killer cell, biology, Immunology, Histocompatibility Antigens Class I, chemical and pharmacologic phenomena, NK cells, Human leukocyte antigen, Major histocompatibility complex, Natural killer T cell, Article, Killer Cells, Natural, 03 medical and health sciences, 030104 developmental biology, MHC class I, biology.protein, Interleukin 12, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunology and Allergy, Humans, Fatal attraction, CD8
Abstract

The activating NK-cell receptor KIR3DS1 has been implicated in the outcome of various human diseases, including delayed HIV-1 disease progression, yet a ligand that accounts for its biological effects remained unknown. We screened 100 HLA-I proteins and found that KIR3DS1 binds HLA-F, which was validated biochemically and functionally. Primary human KIR3DS1+ NK cells degranulated and produced antiviral cytokines upon encountering HLA-F, and inhibited HIV-1 replication in vitro. CD4+ T-cell activation triggered HLA-F transcription and expression and induced KIR3DS1 ligand expression. HIV-1 infection further increased HLA-F transcription, but decreased KIR3DS1 ligand expression, indicating an immune-evasion mechanism. Altogether, we established HLA-F as a ligand of KIR3DS1, and demonstrated cell-context-dependent expression of HLA-F that may explain the widespread influence of KIR3DS1 in human diseases.

Published
2016

41. Science Signaling Podcast for 3 May 2016: Innate lymphoid cell plasticity

Author

Eric Vivier, Annalisa M. VanHook, and Rachel Golub

Subjects
0301 basic medicine, Innate lymphoid cell, Notch signaling pathway, Cell Biology, Biology, Acquired immune system, Biochemistry, Cell biology, Mouse Intestine, 03 medical and health sciences, Heterogeneous population, 030104 developmental biology, Immune system, Immunology, Signal transduction, Molecular Biology, Transforming growth factor
Abstract

This Podcast features an interview with Rachel Golub and Eric Vivier, authors of two Research Articles that appear in the 3 May 2016 issue of Science Signaling, about plasticity of innate lymphoid cells (ILCs). ILCs are related to the T cells and B cells of the adaptive immune system, and they regulate immune responses by secreting cytokines. ILCs are a heterogeneous population of cells that can be classified into several subtypes. Type 3 ILCs (ILC3s) can be further subdivided into distinct subpopulations. Chea et al found that Notch signaling controlled the relative proportions of different ILC3 subtypes in the mouse intestine. A related study by Viant et al reports that the Notch and transforming growth factor-β (TGF-β) signaling pathways antagonize one another to control the balance between different subsets of ILC3s. Both studies demonstrate that ILC3 fate is plastic and can be influenced by signals present in the microenvironment of these tissue-resident cells.Listen to Podcast.

Published
2016

42. Notch signaling in group 3 innate lymphoid cells modulates their plasticity

Author

James P. Di Santo, Sylvestre Chea, Ana Cumano, Thibaut Perchet, Thomas Verrier, Delphine Guy-Grand, Rachel Golub, Christian A. J. Vosshenrich, Maxime Petit, Elena Gaia Banchi, Cellule Pasteur, PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité Innée, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the Pasteur Institute, INSERM, Université Paris Diderot, and the Ministère de la Recherche (to S.C. and T.V.), the Association pour la Recherche sur le Cancer (to S.C. and R.G.), the REVIVE Future Investment Program and the Agence Nationale de la Recherche (ANR) (grant 'Twothyme') (to A.C.), the Ligue Nationale contre le Cancer (to J.P.D.S. and T.V.), the ANR (grant 'Myeloten') (to R.G.), and the Institut National du Cancer (grant 'Role of the immune microenvironment during liver carcinogenesis') (to R.G.) and the Université Sorbonne Paris Cité (grant 'Mucocell'), ANR-14-CE11-0022,Twothyme,Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T.(2014), ANR-13-ISV1-0003,MYELOTEN,DEREGULATION DE L'HEMATOPOIESE PAR LA SUREXPRESSION DE L'INTERLEUKINE-10 : IMPLICATIONS DANS LE DEVELOPPEMENT DE PATHOLOGIES HEMATOLOGIQUES(2013), Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité Innée - Innate Immunity, and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, viruses, Population, Notch signaling pathway, Biology, Cell fate determination, Biochemistry, 03 medical and health sciences, Mice, 0302 clinical medicine, Transforming Growth Factor beta, Animals, Humans, Cell Lineage, Lymphocytes, education, Molecular Biology, Transcription factor, Cells, Cultured, Cell Proliferation, Mice, Knockout, education.field_of_study, Innate immune system, Receptors, Notch, Effector, Interleukins, Innate lymphoid cell, virus diseases, Cell Biology, Aryl hydrocarbon receptor, Immunity, Innate, Cell biology, Intestines, 030104 developmental biology, Immunology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, 030215 immunology, Signal Transduction
Abstract

International audience; The Notch signaling pathway is conserved throughout evolution, and it controls various processes, including cell fate determination, differentiation, and proliferation. Innate lymphoid cells (ILCs) are lymphoid cells lacking antigen receptors that fulfill effector and regulatory functions in innate immunity and tissue remodeling. Type 3 ILCs (ILC3s) reinforce the epithelial barrier and maintain homeostasis with intestinal microbiota. We demonstrated that the population of natural cytotoxicity receptor-positive (NCR(+)) ILC3s in mice is composed of two subsets that have distinct developmental requirements. A major subset depended on the activation of Notch2 in NCR(-) ILC3 precursors in the lamina propria of the small intestine to stimulate expression of the genes encoding the transcription factors T-bet, RORγt, and aryl hydrocarbon receptor (AhR). Notch signaling contributed to the transition of NCR(-) cells into NCR(+) cells, the more proinflammatory subset, in a cell-autonomous manner. In the absence of Notch signaling, this subset of NCR(-) ILC3s did not acquire the gene expression profile of NCR(+) ILC3s. A second subset of NCR(+) ILC3s did not depend on Notch for their development or for increased transcription factor abundance; however, their production of cytokines and cell surface abundance of NCRs were decreased in the absence of Notch signaling. Together, our data suggest that Notch is a regulator of the plasticity of ILC3s by controlling NCR(+) cell fate.

Published
2016

43. Fetal B Cell Development

Author

Rachel Golub, Paulo Vieira, Ana Cumano, and Pablo Pereira

Subjects
medicine.medical_specialty, Myeloid, biology, Cell biology, Haematopoiesis, medicine.anatomical_structure, Endocrinology, Terminal deoxynucleotidyl transferase, Internal medicine, medicine, biology.protein, Lymphopoiesis, Progenitor cell, Antibody, Stem cell, B cell
Abstract

During embryonic development, B cell production occurs in the fetal liver (FL). Newly generated hematopoietic progenitors migrate to the FL starting at E10.5 where they not only mature into hematopoietic stem cells, but also differentiate giving rise to lymphoid progenitors. Lymphoid progenitors, characterized by the expression of the alpha chain of the interleukin-7 receptor only lose myeloid potential after E12.5 and rapidly differentiate to give rise to the first detectable CD19-expressing committed-B cell progenitors at E13.5. Although immunoglobulin heavy chain gene rearrangements are found in E13.5 FL, the first immunoglobulin expressing cells are only detectable near birth (E17.5). The main characteristics distinguishing B cell development in FL from that in bone marrow are (1) Expression of Lin28b, a regulator of the microRNA let 7 family, that may be involved in the preferential capacity of FL cells to generate B1 B cells; (2) Insensitivity to estrogens, due to the absence of estrogen receptors in fetal precursors; (3) Partial independence of interleukin-7 to progress in the B cell pathway of differentiation; and (4) Absence of N sequences at the immunoglobulin genes due to the low expression of the enzyme terminal deoxynucleotidyl transferase, resulting in a restricted B cell receptor repertoire.

Published
2016

44. Fetal spleen stroma drives macrophage commitment

Author

Julien Y. Bertrand, Guillaume E. Desanti, Ana Cumano, Richard Lo-Man, Rachel Golub, and Claude Leclerc

Subjects
T-Lymphocytes, Anti-Inflammatory Agents, Bone Marrow Cells, Spleen, Biology, Mice, Fetus, medicine, Animals, Macrophage, Cell Lineage, Molecular Biology, Cells, Cultured, B cell, Cell Proliferation, B-Lymphocytes, Reverse Transcriptase Polymerase Chain Reaction, Macrophages, Cell Differentiation, Flow Cytometry, Hematopoietic Stem Cells, Immunohistochemistry, Cell biology, Mice, Inbred C57BL, Haematopoiesis, medicine.anatomical_structure, Liver, Immunology, Red pulp, Leukocyte Common Antigens, Erythropoiesis, Stromal Cells, Stem cell, Fetal Spleen, Developmental Biology
Abstract

The role of the fetal spleen in hematopoeisis remains largely unknown. In this particular environment, we show that hematopoietic stem cells do not proliferate, but that they lose multipotency and differentiate exclusively into mature macrophages. B lymphocytes in the spleen derive from committed B cell precursors that are likely to have immigrated from the fetal liver. We developed fetal spleen stromal cell lines that are unique in their capacity to expand myeloid precursors, resulting in large numbers of mature macrophages. These lines secrete high levels of anti-inflammatory molecules. By phenotype,fetal splenic macrophages are reminiscent of their adult counterparts found in the red pulp. We postulate that F4/80+ splenic macrophages participate in fetal erythropoiesis, as well as in the formation of the splenic architecture.

Published
2006

45. Characterization of purified intraembryonic hematopoietic stem cells as a tool to define their site of origin

Author

Laurent Boucontet, Julien Y. Bertrand, Ana Cumano, Isabelle Godin, Abdelali Jalil, Rachel Golub, Michèle Klaine, and Sébastien Giroux

Subjects
Mesoderm, Population, Biology, Mice, Mice, Congenic, medicine, Animals, Cell Lineage, Progenitor cell, Gonads, education, Aorta, education.field_of_study, Multidisciplinary, Macrophages, Lateral plate mesoderm, Hematopoietic stem cell, Biological Sciences, Embryo, Mammalian, Hematopoietic Stem Cells, Embryonic stem cell, Cell biology, Mice, Inbred C57BL, Haematopoiesis, medicine.anatomical_structure, Mesonephros, Immunology, Leukocyte Common Antigens, Stem cell, Biomarkers
Abstract

Little is known about hematopoietic stem cell (HSC) development from mesoderm. To gain more information on the intraembryonic HSC site of origin, we purified multipotent hematopoietic progenitors from the aorta–gonads–mesonephros (AGM) of mice. This population, expressing c-Kit, AA4.1, CD31, and CD41, but not Flk1, and mainly negative for CD45, proved capable of long-term reconstitution in sublethally irradiated Rag2γc -/- recipients. We assigned the expression of GATA-2, GATA-3, and lmo2 to AGM-HSC, whereas erythromyeloid progenitors express only GATA-2. This unique combination of surface markers and transcription factors could be allocated in the AGM to the intraaortic clusters and the subaortic patches underlying aortic endothelial cells. Taken together, those data indicate that embryonic HSCs ( i ) differ from their fetal liver and adult counterpart by the low expression of CD45, ( ii ) do not colocalize with aortic endothelial cells as previously thought, and ( iii ) are localized, at 10.5 days postcoïtum, in the splanchnic mesoderm underlying aortic endothelial cells, within GATA-3 + CD31 + cell clusters.

Published
2004

46. Superantigen-Induced TCR α Locus Secondary Rearrangement: Role in Tolerance Induction

Author

Osami Kanagawa, Ching-Yu Huang, Gillian E. Wu, and Rachel Golub

Subjects
Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, Immunology, Down-Regulation, Cytochrome c Group, Mice, Transgenic, chemical and pharmacologic phenomena, Locus (genetics), Endogeny, Biology, Lymphocyte Activation, Mice, chemistry.chemical_compound, In vivo, hemic and lymphatic diseases, Immune Tolerance, Superantigen, Animals, Immunology and Allergy, Antigens, Columbidae, Gene, Mice, Knockout, Superantigens, T-cell receptor, Cell Differentiation, hemic and immune systems, Molecular biology, biological factors, Mice, Inbred C57BL, Tolerance induction, chemistry, Injections, Intravenous, Mice, Inbred CBA, Immunization, Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor, Genes, T-Cell Receptor alpha, Spleen, DNA
Abstract

Immunization with superantigen in vivo induces transient activation of superantigen-specific T cells, followed by a superantigen-nonresponsive state. In this study, using a TCR α knock-in mouse in which the knock-in α-chain can be replaced with endogenous α-chain through secondary rearrangement, we show that immunization of superantigen changes the TCR α-chain expression on peripheral superantigen-specific T cells, induces expression of recombination-activating genes, and generates DNA double-strand breaks at the TCR α-chain locus. These results suggest that viral superantigens are capable of inducing peripheral TCR revision. Our findings thus provide a new perspective on pathogen-immune system interaction.

Published
2002

48. Stem Cells: From Basic Research to Therapy, Volume 1

Author

Mitsuyasu Hasebe, Hiromi Shimojo, Rachel GOLUB, Ana Alexandre, Abigail Tucker, Federico Calegari, Paulo Vieira, and Teresa Adell

Subjects
Basic research, ved/biology, ved/biology.organism_classification_rank.species, Tissue formation, Biology, Stem cell, Model organism, Stem cell biology, Cell biology
Published
2014

49. Vα gene replacement in a TCRα knock-in mouse

Author

Rachel Golub, Osami Kanagawa, Gillian E. Wu, and Ching-Yu Huang

Subjects
medicine.anatomical_structure, Immune system, Gene replacement, Transgene, T cell, Immunology, T-cell receptor, medicine, Immunology and Allergy, Locus (genetics), Biology, Knock in mouse, Molecular biology
Abstract

Using a TCRα chain knock-in mouse, we demonstrate that V-gene replacement can operate in the T cell receptor α locus. Functional TCRα chain transcripts generated by Vα-gene replacement at the site of the Vα-embedded heptamer were identified in splenic T cells. This finding shows that Vα-gene replacement can likely be used to shape the peripheral T cell repertoire.The conservation of the embedded heptamer in most Vα segments adds support to the notion that V-gene replacement is a mechanism maintained to diversify the immune system and that argues that itis common to B and T cells.

Published
2001

50. Erratum: Corrigendum: Evidence of innate lymphoid cell redundancy in humans

Author

Rachel Golub, Nicolas Zucchini, Gérard Michel, Fabien Touzot, Capucine Picard, Maxime Petit, Stéphane Blanche, Vincent Barlogis, Frédéric Vély, Andreas Ramming, Thibaut Perchet, Nizar Mahlaoui, Blandine Vallentin, Catherine Farnarier, Jörg H W Distler, Arnaud Dujardin, Alain Fischer, Bénédicte Neven, Hergen Spits, Eric Vivier, Nadia Yessaad, Julie Bruneau, Despina Moshous, and Christelle Piperoglou

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, Immunology, Innate lymphoid cell, Redundancy (engineering), Immunology and Allergy, Biology, Classics
Abstract

Nat. Immunol. 17, 1291–1299 (2016); published online 12 September 2016; corrected after print 19 October 2016 In the version of this article initially published, author Mikael Ebbo was missing from the author list. The correct list is as follows: Frederic Vely1,2,20, Vincent Barlogis3,20, Blandine Vallentin3,20, Benedicte Neven4–7,20, Christelle Piperoglou1,2, Mikael Ebbo1,8, Thibaut Perchet9,10, Maxime Petit9,10, Nadia Yessaad11, Fabien Touzot5,12, Julie Bruneau5,13, Nizar Mahlaoui47, Nicolas Zucchini14, Catherine Farnarier2, Gerard Michel3, Despina Moshous47, Stephane Blanche47, Arnaud Dujardin15, Hergen Spits16, Jorg H W Distler17, Andreas Ramming17, Capucine Picard4–7,18, Rachel Golub9,10, Alain Fischer4–7,19,21 & Eric Vivier1,2,21.

Published
2016

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