127 results on '"Cheroutre H"'
Search Results
2. Mucosal effector memory T cells: the other side of the coin
- Author
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Cheroutre, H. and Madakamutil, L.
- Published
- 2005
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3. CD8αα Expression Marks Terminally Differentiated Human CD8+ T Cells Expanded in Chronic Viral Infection
- Author
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Walker, LJ, Marrinan, E, Muenchhoff, M, Ferguson, J, Kloverpris, H, Cheroutre, H, Barnes, E, Goulder, P, and Klenerman, P
- Subjects
CD8α ,Immunology ,HIV-1 ,hepatitis B ,hepatitis C ,CD8+ T cells - Abstract
The T cell co-receptor CD8αβ enhances T cell sensitivity to antigen, however studies indicate CD8αα has the converse effect and acts as a co-repressor. Using a combination of Thymic Leukemia (TL) antigen tetramer, which directly binds CD8αα, anti-CD161, and anti-Vα7.2 antibodies we have been able for the first time to clearly define CD8αα expression on human CD8 T cells subsets. In healthy controls CD8αα is most highly expressed by CD161 "bright" (CD161++) mucosal associated invariant T (MAIT) cells, with CD8αα expression highly restricted to the TCR Vα7.2+ cells of this subset. We also identified CD8αα-expressing populations within the CD161 "mid" (CD161+) and "negative" (CD161-) non-MAIT CD8 T cell subsets and show TL-tetramer binding to correlate with expression of CD8β at low levels in the context of maintained CD8α expression (CD8α+CD8β(low)). In addition, we found CD161-CD8α+CD8β(low) populations to be significantly expanded in the peripheral blood of HIV-1 and hepatitis B (mean of 47 and 40% of CD161- T cells respectively) infected individuals. Such CD8αα expressing T cells are an effector-memory population (CD45RA-, CCR7-, CD62L-) that express markers of activation and maturation (HLA-DR+, CD28-, CD27-, CD57+) and are functionally distinct, expressing greater levels of TNF-α and IFN-γ on stimulation and perforin at rest than their CD8α+CD8β(high) counterparts. Antigen-specific T cells in HLA-B(∗)4201+HIV-1 infected patients are found within both the CD161-CD8α+CD8β(high) and CD161-CD8α+CD8β(low) populations. Overall we have clearly defined CD8αα expressing human T cell subsets using the TL-tetramer, and have demonstrated CD161-CD8α+CD8β(low) populations, highly expanded in disease settings, to co-express CD8αβ and CD8αα. Co-expression of CD8αα on CD8αβ T cells may impact on their overall function in vivo and contribute to the distinctive phenotype of highly differentiated populations in HBV and HIV-1 infection.
- Published
- 2013
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4. Mucosal CD8 Memory T Cells are selected in the periphery by an MHC Class I Molecule
- Author
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Larange, A., Grubeck-Loebenstein, B., Herndler-Brandstätter, D., Olivares-Villagómez, D., Cheroutre, H., Bernardo, I., Van Kaer, L., Kronenberg, M., Teitell, M.A., Abraham, N., Arens, R., Schoenberger, S.P., Huang, Y., and Wang-Zhu, Y.
- Subjects
Biological Sciences - Abstract
The presence of immune memory at pathogen entry sites is a prerequisite for protection. Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood. Here we show that the non-classical MHC class I molecule, the thymus leukemia antigen (TL), induced on dendritic cells together with CD8aa on activated CD8αβ+T cells, mediates affinity-based selection of memory precursor cells. Furthermore, constitutive expression of TL on epithelial cells continues the selection of mature CD8αβ memory T cells. The TL-CD8αα-driven memory process is essential for the generation of memory CD8αß T cells in the intestine and leads to the accumulation of highly antigen sensitive CD8αβ memory T cells that form the first line of defense at the largest entry port for pathogens.
- Published
- 2011
5. NIK-dependent RelB activation defines a unique signaling pathway for the development of Vα14i NKT cells
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Elewaut, D, Shaikh, RB, Hammond, KJL, De Winter, H, Leishman, AJ, Sidobre, S, Turovskaya, O, Prigozy, TI, Ma, L, Banks, TA, Lo, D, Ware, CF, Cheroutre, H, and Kronenberg, M
- Subjects
chemical and pharmacologic phenomena ,hemic and immune systems - Abstract
A defect in RelB, a member of the Rel/nuclear factor (NF)-κB family of transcription factors, affects antigen presenting cells and the formation of lymphoid organs, but its role in T lymphocyte differentiation is not well characterized. Here, we show that RelB deficiency in mice leads to a selective decrease of NKT cells. RelB must be expressed in an irradiation-resistant host cell that can be CD1d negative, indicating that the RelB expressing cell does not contribute directly to the positive selection of CD1d-dependent NKT cells. Like RelB-deficient mice, aly/aly mice with a mutation for the NF-κB-inducing kinase (NIK), have reduced NKT cell numbers. An analysis of NK1.1 and CD44 expression on NKT cells in the thymus of aly/aly mice reveals a late block in development. In vitro, we show that NIK is necessary for RelB activation upon triggering of surface receptors. This link between NIK and RelB was further demonstrated in vivo by analyzing RelB+/-X aly/+ compound heterozygous mice. After stimulation with α-GalCer, an antigen recognized by NKT cells, these compound heterozygotes had reduced responses compared with either RelB+/-or aly/+ mice. These data illustrate the complex interplay between hemopoietic and nonhemopoietic cell types for the development of NKT cells, and they demonstrate the unique requirement of NKT cells for a signaling pathway mediated by NIK activation of RelB in a thymic stromal cell.
- Published
- 2003
6. Unique lamina propria stromal cells imprint the functional phenotype of mucosal dendritic cells.
- Author
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Vicente-Suarez, I, Larange, A, Reardon, C, Matho, M, Feau, S, Chodaczek, G, Park, Y, Obata, Y, Gold, R, Wang-Zhu, Y, Lena, C, Zajonc, D M, Schoenberger, S P, Kronenberg, M, and Cheroutre, H
- Published
- 2015
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7. Following the fate of one insulin-reactive CD4 T cell: conversion into Teffs and Tregs in the periphery controls diabetes in NOD mice.
- Author
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Fousteri G, Jasinski J, Dave A, Nakayama M, Pagni P, Lambolez F, Juntti T, Sarikonda G, Cheng Y, Croft M, Cheroutre H, Eisenbarth G, von Herrath M, Fousteri, Georgia, Jasinski, Jean, Dave, Amy, Nakayama, Maki, Pagni, Philippe, Lambolez, Florence, and Juntti, Therese
- Abstract
In diabetic patients and susceptible mice, insulin is a targeted autoantigen. Insulin B chain 9-23 (B:9-23) autoreactive CD4 T cells are key for initiating autoimmune diabetes in NOD mice; however, little is known regarding their origin and function. To this end, B:9-23-specific, BDC12-4.1 T-cell receptor (TCR) transgenic (Tg) mice were studied, of which, despite expressing a single TCR on the recombination activating gene-deficient background, only a fraction develops diabetes in an asynchronous manner. BDC12-4.1 CD4 T cells convert into effector (Teff) and Foxp3(+)-expressing adaptive regulatory T cells (aTregs) soon after leaving the thymus as a result of antigen recognition and homeostatic proliferation. The generation of aTreg causes the heterogeneous diabetes onset, since crossing onto the scurfy (Foxp3) mutation, BDC12-4.1 TCR Tg mice develop accelerated and fully penetrant diabetes. Similarly, adoptive transfer and bone marrow transplantation experiments showed differential diabetes kinetics based on Foxp3(+) aTreg's presence in the BDC12-4.1 donors. A single-specificity, insulin-reactive TCR escapes thymic deletion and simultaneously converts into aTreg and Teff, establishing an equilibrium that determines diabetes penetrance. These results are of particular importance for understanding disease pathogenesis. They suggest that once central tolerance is bypassed, autoreactive cells arriving in the periphery do not by default follow solely a pathogenic fate upon activation. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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8. Regulatory T-cell stability and plasticity in mucosal and systemic immune systems.
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Murai, M, Krause, P, Cheroutre, H, and Kronenberg, M
- Published
- 2010
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9. T-cell production of an inducible interleukin-10 transgene provides limited protection from autoimmune diabetes.
- Author
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Pauza, Mary E., Neal, Heather, Hagenbaugh, Amy, Cheroutre, Hilde, Lo, David, Pauza, M E, Neal, H, Hagenbaugh, A, Cheroutre, H, and Lo, D
- Subjects
INTERLEUKIN-10 ,T cells ,DIABETES - Abstract
In a number of animal models of spontaneous autoimmune diabetes, pathogenesis has been highly correlated with autoreactive T-cell production of the type 1 cytokine interferon-gamma (IFN-gamma), while protection from disease was associated with type 2 cytokines such as interleukin (IL)-4. Curiously, in some models, diabetes is associated with unexpected cytokine patterns; for example, diabetes can develop in NOD mice lacking a functional IFN-gamma gene. In another situation, acceleration of diabetes occurs in transgenic mice with constitutive beta-cell expression of the type 2 cytokine IL-10. IL-10 has generally been associated with immunosuppression, including the modulation of class II expression on antigen-presenting cells and the generation of regulatory CD4 T-cells. Because it is possible that unregulated expression of any cytokine might lead to unphysiological effects in vivo, we tested the notion that an inducible T-cell-specific IL-10 transgene might yet mediate a more physiological protection from autoimmune diabetes. Our results show that indeed, regulated T-cell production of IL-10 does not accelerate diabetes and instead can provide significant protection from disease. These results help rectify the apparent discrepancies between the effect of IL-10 on various models of autoimmune diabetes. [ABSTRACT FROM AUTHOR]
- Published
- 1999
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10. Transgenic Mice Expressing a Truncated Peromyscus leucopus TNF-a Gene Manifest an Arthritis Resembling Ankylosing Spondylitis
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Crew, M. D., Effros, R. B., Walford, R. L., Zeller, E., Cheroutre, H., and Brahn, E.
- Published
- 1998
11. A simple apparatus for injection of nanoliter quantities into Xenopus laevis oocytes
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Contreras, R., Cheroutre, H., and Fiers, W.
- Published
- 1981
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12. HIGH LEVEL SYNTHESIS OF PROTEINS IN HETEROLOGOUS CELLS USING GENETIC ENGINEERING APPROACHES
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Fiers, W., Remaut, E., Stanssens, P., Simons, G., Scahill, S., Cheroutre, H., Plaetinck, G., Tavernier, J., Degrave, W., Duerinck, F., Devos, R., and Van der Heyden, J.
- Published
- 1984
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13. Intra-tumoral T cells in pediatric brain tumors display clonal expansion and effector properties.
- Author
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Upadhye A, Meza Landeros KE, Ramírez-Suástegui C, Schmiedel BJ, Woo E, Chee SJ, Malicki D, Coufal NG, Gonda D, Levy ML, Greenbaum JA, Seumois G, Crawford J, Roberts WD, Schoenberger SP, Cheroutre H, Ottensmeier CH, Vijayanand P, and Ganesan AP
- Subjects
- Humans, Child, Antigens, Neoplasm immunology, Immunotherapy methods, Child, Preschool, Male, Female, Adolescent, Lymphocytes, Tumor-Infiltrating immunology, Single-Cell Analysis methods, Transcriptome, Clone Cells, Brain Neoplasms immunology, Brain Neoplasms pathology, Brain Neoplasms genetics, T-Lymphocytes immunology
- Abstract
Brain tumors in children are a devastating disease in a high proportion of patients. Owing to inconsistent results in clinical trials in unstratified patients, the role of immunotherapy remains unclear. We performed an in-depth survey of the single-cell transcriptomes and clonal relationship of intra-tumoral T cells from children with brain tumors. Our results demonstrate that a large fraction of T cells in the tumor tissue are clonally expanded with the potential to recognize tumor antigens. Such clonally expanded T cells display enrichment of transcripts linked to effector function, tissue residency, immune checkpoints and signatures of neoantigen-specific T cells and immunotherapy response. We identify neoantigens in pediatric brain tumors and show that neoantigen-specific T cell gene signatures are linked to better survival outcomes. Notably, among the patients in our cohort, we observe substantial heterogeneity in the degree of clonal expansion and magnitude of T cell response. Our findings suggest that characterization of intra-tumoral T cell responses may enable selection of patients for immunotherapy, an approach that requires prospective validation in clinical trials., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2024
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14. Transcriptomes and metabolism define mouse and human MAIT cell populations.
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Chandra S, Ascui G, Riffelmacher T, Chawla A, Ramírez-Suástegui C, Castelan VC, Seumois G, Simon H, Murray MP, Seo GY, Premlal ALR, Schmiedel B, Verstichel G, Li Y, Lin CH, Greenbaum J, Lamberti J, Murthy R, Nigro J, Cheroutre H, Ottensmeier CH, Hedrick SM, Lu LF, Vijayanand P, and Kronenberg M
- Subjects
- Humans, Transcriptome, CD8-Positive T-Lymphocytes, Thymus Gland, Lipids, Mucosal-Associated Invariant T Cells
- Abstract
Mucosal-associated invariant T (MAIT) cells are a subset of T lymphocytes that respond to microbial metabolites. We defined MAIT cell populations in different organs and characterized the developmental pathway of mouse and human MAIT cells in the thymus using single-cell RNA sequencing and phenotypic and metabolic analyses. We showed that the predominant mouse subset, which produced IL-17 (MAIT17), and the subset that produced IFN-γ (MAIT1) had not only greatly different transcriptomes but also different metabolic states. MAIT17 cells in different organs exhibited increased lipid uptake, lipid storage, and mitochondrial potential compared with MAIT1 cells. All these properties were similar in the thymus and likely acquired there. Human MAIT cells in lung and blood were more homogeneous but still differed between tissues. Human MAIT cells had increased fatty acid uptake and lipid storage in blood and lung, similar to human CD8 T resident memory cells, but unlike mouse MAIT17 cells, they lacked increased mitochondrial potential. Although mouse and human MAIT cell transcriptomes showed similarities for immature cells in the thymus, they diverged more strikingly in the periphery. Analysis of pet store mice demonstrated decreased lung MAIT17 cells in these so-called "dirty" mice, indicative of an environmental influence on MAIT cell subsets and function.
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- 2023
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15. A regulatory circuit controlled by extranuclear and nuclear retinoic acid receptor α determines T cell activation and function.
- Author
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Larange A, Takazawa I, Kakugawa K, Thiault N, Ngoi S, Olive ME, Iwaya H, Seguin L, Vicente-Suarez I, Becart S, Verstichel G, Balancio A, Altman A, Chang JT, Taniuchi I, Lillemeier B, Kronenberg M, Myers SA, and Cheroutre H
- Subjects
- Humans, Retinoic Acid Receptor alpha genetics, Cell Membrane, Receptors, Antigen, T-Cell, Lymphocyte Activation, Autoimmune Diseases
- Abstract
Ligation of retinoic acid receptor alpha (RARα) by RA promotes varied transcriptional programs associated with immune activation and tolerance, but genetic deletion approaches suggest the impact of RARα on TCR signaling. Here, we examined whether RARα would exert roles beyond transcriptional regulation. Specific deletion of the nuclear isoform of RARα revealed an RARα isoform in the cytoplasm of T cells. Extranuclear RARα was rapidly phosphorylated upon TCR stimulation and recruited to the TCR signalosome. RA interfered with extranuclear RARα signaling, causing suboptimal TCR activation while enhancing FOXP3
+ regulatory T cell conversion. TCR activation induced the expression of CRABP2, which translocates RA to the nucleus. Deletion of Crabp2 led to increased RA in the cytoplasm and interfered with signalosome-RARα, resulting in impaired anti-pathogen immunity and suppressed autoimmune disease. Our findings underscore the significance of subcellular RA/RARα signaling in T cells and identify extranuclear RARα as a component of the TCR signalosome and a determinant of immune responses., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
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16. CD4 + -mediated colitis in mice is independent of the GPR183 and GPR18 pathways.
- Author
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Dicker M, Li Y, Giles DA, Verstichel G, Castelan VC, Ascui-Gac G, Chou TF, Perez-Jeldres T, Cheroutre H, and Kronenberg M
- Subjects
- Mice, Humans, Animals, Dextran Sulfate adverse effects, Mice, Inbred C57BL, Disease Models, Animal, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, CD4-Positive T-Lymphocytes metabolism, Genome-Wide Association Study, Colitis chemically induced, Colitis genetics
- Abstract
Colitis is characterized by an exacerbated intestinal immune response, but the genetic and other mechanisms regulating immune activation remain incompletely understood. In order to identify new pathways leading to colitis, we sought to identify genes with increased expression in the colons of patients that also are near loci identified by genome wide association studies (GWAS) associated with IBD risk. One such SNP, rs9557195 was of particular interest because it is within an intron of G-protein-coupled receptor (GPR) 183 , known to be important for lymphocyte migration. Furthermore, this SNP is in close proximity to the gene encoding another G-protein coupled receptor, GPR18 . Analyzing publicly available datasets, we found transcripts of GPR183 and GPR18 to be increased in colon biopsies from ulcerative colitis and Crohn's disease patients, and GPR183 was even more increased in patients resistant to TNF treatment. Expression of both genes also was increased in mouse models of colitis. Therefore, our aim was to understand if increased expression of these GPRs in the intestine is related to disease severity in colitis models. Here we investigated the role of these receptors in the T cell transfer model and the dextran sulfate sodium model. In the T cell transfer model, GPR183 expression on donor T cells, as well as on other cell types in the Rag
-/- recipients, was not essential for severe colitis induction. Furthermore, deficiency in Rag-/- mice for the enzyme that synthesizes a cholesterol metabolite that is a major ligand for GPR183 also did not affect disease. Similarly, lack of GPR18 expression in T cells or other cell types did not affect colitis pathogenesis in the T cell transfer or in the dextran sulfate sodium model. Therefore, despite increased expression of transcripts for these genes in the intestine during inflammation in humans and mice, they are not required for disease severity in mouse models of colitis induced by chemical injury or T cell cytokines, perhaps due to redundancy in mechanisms important for homing and survival of lymphocytes to the inflamed intestine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dicker, Li, Giles, Verstichel, Castelan, Ascui-Gac, Chou, Perez-Jeldres, Cheroutre and Kronenberg.)- Published
- 2022
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17. Epithelial HVEM maintains intraepithelial T cell survival and contributes to host protection.
- Author
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Seo GY, Takahashi D, Wang Q, Mikulski Z, Chen A, Chou TF, Marcovecchio P, McArdle S, Sethi A, Shui JW, Takahashi M, Surh CD, Cheroutre H, and Kronenberg M
- Subjects
- Animals, Collagen, Epithelial Cells metabolism, Integrins metabolism, Ligands, Mice, Intraepithelial Lymphocytes
- Abstract
Intraepithelial T cells (IETs) are in close contact with intestinal epithelial cells and the underlying basement membrane, and they detect invasive pathogens. How intestinal epithelial cells and basement membrane influence IET survival and function, at steady state or after infection, is unclear. The herpes virus entry mediator (HVEM), a member of the TNF receptor superfamily, is constitutively expressed by intestinal epithelial cells and is important for protection from pathogenic bacteria. Here, we showed that at steady-state LIGHT, an HVEM ligand, binding to epithelial HVEM promoted the survival of small intestine IETs. RNA-seq and addition of HVEM ligands to epithelial organoids indicated that HVEM increased epithelial synthesis of basement membrane proteins, including collagen IV, which bound to β
1 integrins expressed by IETs. Therefore, we proposed that IET survival depended on β1 integrin binding to collagen IV and showed that β1 integrin-collagen IV interactions supported IET survival in vitro. Moreover, the absence of β1 integrin expression by T lymphocytes decreased TCR αβ+ IETs in vivo. Intravital microscopy showed that the patrolling movement of IETs was reduced without epithelial HVEM. As likely consequences of decreased number and movement, protective responses to Salmonella enterica were reduced in mice lacking either epithelial HVEM, HVEM ligands, or β1 integrins. Therefore, IETs, at steady state and after infection, depended on HVEM expressed by epithelial cells for the synthesis of collagen IV by epithelial cells. Collagen IV engaged β1 integrins on IETs that were important for their maintenance and for their protective function in mucosal immunity.- Published
- 2022
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18. HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160.
- Author
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Liu W, Chou TF, Garrett-Thomson SC, Seo GY, Fedorov E, Ramagopal UA, Bonanno JB, Wang Q, Kim K, Garforth SJ, Kakugawa K, Cheroutre H, Kronenberg M, and Almo SC
- Subjects
- Animals, Antigens, CD chemistry, Antigens, CD genetics, Crystallography, X-Ray, Drosophila cytology, Drosophila genetics, Female, GPI-Linked Proteins chemistry, GPI-Linked Proteins genetics, GPI-Linked Proteins metabolism, Male, Mice, Inbred C57BL, Mice, Transgenic, Multiprotein Complexes chemistry, Multiprotein Complexes metabolism, Mutation, Receptors, Immunologic chemistry, Receptors, Immunologic genetics, Receptors, Tumor Necrosis Factor, Member 14 genetics, Tumor Necrosis Factor Ligand Superfamily Member 14 chemistry, Tumor Necrosis Factor Ligand Superfamily Member 14 genetics, Yersinia Infections genetics, Yersinia Infections pathology, Mice, Antigens, CD metabolism, Receptors, Immunologic metabolism, Receptors, Tumor Necrosis Factor, Member 14 chemistry, Receptors, Tumor Necrosis Factor, Member 14 metabolism, Tumor Necrosis Factor Ligand Superfamily Member 14 metabolism
- Abstract
HVEM is a TNF (tumor necrosis factor) receptor contributing to a broad range of immune functions involving diverse cell types. It interacts with a TNF ligand, LIGHT, and immunoglobulin (Ig) superfamily members BTLA and CD160. Assessing the functional impact of HVEM binding to specific ligands in different settings has been complicated by the multiple interactions of HVEM and HVEM binding partners. To dissect the molecular basis for multiple functions, we determined crystal structures that reveal the distinct HVEM surfaces that engage LIGHT or BTLA/CD160, including the human HVEM-LIGHT-CD160 ternary complex, with HVEM interacting simultaneously with both binding partners. Based on these structures, we generated mouse HVEM mutants that selectively recognized either the TNF or Ig ligands in vitro. Knockin mice expressing these muteins maintain expression of all the proteins in the HVEM network, yet they demonstrate selective functions for LIGHT in the clearance of bacteria in the intestine and for the Ig ligands in the amelioration of liver inflammation., Competing Interests: Disclosures: W. Liu reported a patent to HVEM mutants and applications pending. S.C. Garrett-Thomson reported a patent to HVEM muteins technology pending. S.C. Almo reported a patent to HVEM mutants pending. No other disclosures were reported., (© 2021 Liu et al.)
- Published
- 2021
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19. LIGHT-HVEM Signaling in Innate Lymphoid Cell Subsets Protects Against Enteric Bacterial Infection.
- Author
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Seo GY, Shui JW, Takahashi D, Song C, Wang Q, Kim K, Mikulski Z, Chandra S, Giles DA, Zahner S, Kim PH, Cheroutre H, Colonna M, and Kronenberg M
- Subjects
- Adoptive Transfer, Adult, Animals, Cytokines metabolism, Disease Models, Animal, Enterobacteriaceae Infections pathology, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Host-Pathogen Interactions immunology, Host-Pathogen Interactions physiology, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neuropeptides metabolism, Protein Transport, Receptors, CCR6 genetics, Receptors, CCR6 metabolism, Receptors, Tumor Necrosis Factor metabolism, Spleen microbiology, Spleen pathology, Yersinia enterocolitica pathogenicity, Enterobacteriaceae Infections prevention & control, Interferon-gamma metabolism, Lymphocytes immunology, Lymphocytes metabolism, Receptors, Tumor Necrosis Factor, Member 14 immunology, Receptors, Tumor Necrosis Factor, Member 14 metabolism, Signal Transduction, Tumor Necrosis Factor Ligand Superfamily Member 14 metabolism
- Abstract
Innate lymphoid cells (ILCs) are important regulators of early infection at mucosal barriers. ILCs are divided into three groups based on expression profiles, and are activated by cytokines and neuropeptides. Yet, it remains unknown if ILCs integrate other signals in providing protection. We show that signaling through herpes virus entry mediator (HVEM), a member of the tumor necrosis factor (TNF) receptor superfamily, in ILC3 is important for host defense against oral infection with the bacterial pathogen Yersinia enterocolitica. HVEM stimulates protective interferon-γ (IFN-γ) secretion from ILCs, and mice with HVEM-deficient ILC3 exhibit reduced IFN-γ production, higher bacterial burdens and increased mortality. In addition, IFN-γ production is critical as adoptive transfer of wild-type but not IFN-γ-deficient ILC3 can restore protection to mice lacking ILCs. We identify the TNF superfamily member, LIGHT, as the ligand inducing HVEM signals in ILCs. Thus HVEM signaling mediated by LIGHT plays a critical role in regulating ILC3-derived IFN-γ production for protection following infection. VIDEO ABSTRACT., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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20. Charles D. Surh, PhD: 1961-2017.
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Cheroutre H
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- History, 20th Century, History, 21st Century, Homeostasis, Humans, Korea, Male, United States, Allergy and Immunology history, Immune Tolerance, T-Lymphocytes immunology
- Published
- 2018
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21. Mast cells promote small bowel cancer in a tumor stage-specific and cytokine-dependent manner.
- Author
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Saadalla AM, Osman A, Gurish MF, Dennis KL, Blatner NR, Pezeshki A, McNagny KM, Cheroutre H, Gounari F, and Khazaie K
- Subjects
- Animals, Cells, Cultured, Intestinal Neoplasms immunology, Intestinal Neoplasms metabolism, Intestine, Small immunology, Intestine, Small metabolism, Lymphocytes immunology, Lymphocytes metabolism, Mast Cells immunology, Mast Cells metabolism, Mice, Mucous Membrane immunology, Mucous Membrane metabolism, Neoplasm Staging, Chymases metabolism, Cytokines metabolism, Intestinal Neoplasms pathology, Intestine, Small pathology, Lymphocytes pathology, Mast Cells pathology, Mucous Membrane pathology
- Abstract
Mast cells (MCs) are tissue resident sentinels that mature and orchestrate inflammation in response to infection and allergy. While they are also frequently observed in tumors, the contribution of MCs to carcinogenesis remains unclear. Here, we show that sequential oncogenic events in gut epithelia expand different types of MCs in a temporal-, spatial-, and cytokine-dependent manner. The first wave of MCs expands focally in benign adenomatous polyps, which have elevated levels of IL-10, IL-13, and IL-33, and are rich in type-2 innate lymphoid cells (ILC2s). These vanguard MCs adhere to the transformed epithelial cells and express murine mast cell protease 2 (mMCP2; a typical mucosal MC protease) and, to a lesser extent, the connective tissue mast cell (CTMC) protease mMCP6. Persistence of MCs is strictly dependent on T cell-derived IL-10, and their loss in the absence of IL-10-expressing T cells markedly delays small bowel (SB) polyposis. MCs expand profusely in polyposis-prone mice when T cells overexpress IL-10. The frequency of polyp-associated MCs is unaltered in response to broad-spectrum antibiotics, arguing against a microbial component driving their recruitment. Intriguingly, when polyps become invasive, a second wave of mMCP5
+ /mMCP6+ CTMCs expands in the tumor stroma and at invasive tumor borders. Ablation of mMCP6 expression attenuates polyposis, but invasive properties of the remaining lesions remain intact. Our findings argue for a multistep process in SB carcinogenesis in which distinct MC subsets, and their elaborated proteases, guide disease progression., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)- Published
- 2018
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22. The checkpoint for agonist selection precedes conventional selection in human thymus.
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Verstichel G, Vermijlen D, Martens L, Goetgeluk G, Brouwer M, Thiault N, Van Caeneghem Y, De Munter S, Weening K, Bonte S, Leclercq G, Taghon T, Kerre T, Saeys Y, Van Dorpe J, Cheroutre H, and Vandekerckhove B
- Abstract
The thymus plays a central role in self-tolerance, partly by eliminating precursors with a T cell receptor (TCR) that binds strongly to self-antigens. However, the generation of self-agonist-selected lineages also relies on strong TCR signaling. How thymocytes discriminate between these opposite outcomes remains elusive. Here, we identified a human agonist-selected PD-1
+ CD8αα+ subset of mature CD8αβ+ T cells that displays an effector phenotype associated with agonist selection. TCR stimulation of immature post-β-selection thymocyte blasts specifically gives rise to this innate subset and fixes early T cell receptor alpha variable (TRAV) and T cell receptor alpha joining (TRAJ) rearrangements in the TCR repertoire. These findings suggest that the checkpoint for agonist selection precedes conventional selection in the human thymus., (Copyright © 2017, American Association for the Advancement of Science.)- Published
- 2017
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23. Critical Role of Glucose Metabolism in Rheumatoid Arthritis Fibroblast-like Synoviocytes.
- Author
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Garcia-Carbonell R, Divakaruni AS, Lodi A, Vicente-Suarez I, Saha A, Cheroutre H, Boss GR, Tiziani S, Murphy AN, and Guma M
- Subjects
- Animals, Arthritis, Rheumatoid etiology, Fibroblasts, Glycolysis, Humans, Mice, Arthritis, Rheumatoid metabolism, Glucose metabolism, Synoviocytes metabolism
- Abstract
Objective: Up-regulation of glucose metabolism has been implicated not only in tumor cell growth but also in immune cells upon activation. However, little is known about the metabolite profile in rheumatoid arthritis (RA), particularly in fibroblast-like synoviocytes (FLS). This study was undertaken to evaluate whether changes in glucose metabolism in RA FLS could play a role in inflammation and joint damage., Methods: Synovium and FLS were obtained from patients with RA and patients with osteoarthritis (OA). The rate of glycolysis after stimulation of FLS with lipopolysaccharide and platelet-derived growth factor BB was measured using glycolysis stress test technology. FLS function was evaluated using a glycolysis inhibitor, 2-deoxy-d-glucose (2-DG). After stimulation of the FLS, a migration scratch assay, MTT assay, and enzyme-linked immunosorbent assay were performed to measure the effect of 2-DG on FLS migration, viability of the FLS, and cytokine secretion, respectively. IRDye 800CW 2-DG was used to assess glucose uptake in the arthritic joints and stromal cells of mice after K/BxN mouse serum transfer. The mice were injected daily, intraperitoneally, with 3-bromopyruvate (BrPa; 5 mg/kg) to assess the effect of inhibition of glycolysis in vivo., Results: Compared to human OA FLS, the balance between glycolysis and oxidative phosphorylation was shifted toward glycolysis in RA FLS. Glucose transporter 1 (GLUT1) messenger RNA (mRNA) expression correlated with baseline functions of the RA FLS. Glucose deprivation or incubation of the FLS with glycolytic inhibitors impaired cytokine secretion and decreased the rate of proliferation and migration of the cells. In a mouse model of inflammatory arthritis, GLUT1 mRNA expression in the synovial lining cells was observed, and increased levels of glucose uptake and glycolytic gene expression were detected in the stromal compartment of the arthritic mouse joints. Inhibition of glycolysis by BrPa, administered in vivo, significantly decreased the severity of arthritis in this mouse model., Conclusion: Targeting metabolic pathways is a novel approach to understanding the mechanisms of disease. Inhibition of glycolysis may directly modulate synoviocyte-mediated inflammatory functions and could be an effective treatment strategy for arthritis., (© 2016, American College of Rheumatology.)
- Published
- 2016
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24. Retinoic Acid and Retinoic Acid Receptors as Pleiotropic Modulators of the Immune System.
- Author
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Larange A and Cheroutre H
- Subjects
- Adaptive Immunity, Animals, Humans, Immunity, Innate, Immunomodulation, Receptors, Retinoic Acid metabolism, Tretinoin immunology, Immune System, Intestinal Mucosa physiology, Receptors, Retinoic Acid immunology, Tretinoin metabolism, Vitamin A immunology
- Abstract
Vitamin A is a multifunctional vitamin implicated in a wide range of biological processes. Its control over the immune system and functions are perhaps the most pleiotropic not only for development but also for the functional fate of almost every cell involved in protective or regulatory adaptive or innate immunity. This is especially key at the intestinal border, where dietary vitamin A is first absorbed. Most effects of vitamin A are exerted by its metabolite, retinoic acid (RA), which through ligation of nuclear receptors controls transcriptional expression of RA target genes. In addition to this canonical function, RA and RA receptors (RARs), either as ligand-receptor or separately, play extranuclear, nongenomic roles that greatly expand the multiple mechanisms employed for their numerous and paradoxical functions that ultimately link environmental sensing with immune cell fate. This review discusses RA and RARs and their complex roles in innate and adaptive immunity.
- Published
- 2016
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25. T-cell Expression of IL10 Is Essential for Tumor Immune Surveillance in the Small Intestine.
- Author
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Dennis KL, Saadalla A, Blatner NR, Wang S, Venkateswaran V, Gounari F, Cheroutre H, Weaver CT, Roers A, Egilmez NK, and Khazaie K
- Subjects
- Adoptive Transfer, Animals, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Immunologic Surveillance, Interleukin-10 immunology, Intestinal Neoplasms immunology, Intestine, Small pathology, T-Lymphocytes, Regulatory immunology
- Abstract
IL10 is attributed with immune-suppressive and anti-inflammatory properties, which could promote or suppress cancer in the gastrointestinal tract. Loss of IL10 exacerbates colonic inflammation, leading to colitis and cancer. Consistent with this, transfer of IL10-competent regulatory T cells (Treg) into mice with colitis or hereditary polyposis protects against disease, while IL10-deficient mice are predisposed to polyposis with increased colon polyp load. Little is known about the protective or pathogenic function of IL10 in cancers of the small intestine. We found CD4(+) T cells and CD4(+) Foxp3(+) Tregs to be the major sources of IL10 in the small intestine and responsible for the increase in IL10 during polyposis in the APC(Δ468) mouse model of hereditary polyposis. Targeted ablation of IL10 in T cells caused severe IL10 deficiency and delayed polyp growth. However, these polyps progressively lost cytotoxic activity and eventually progressed to cancer. Several observations suggested that the effect was due to the loss of IFNγ-dependent immune surveillance. IL10-incompetent CD4(+) T cells failed to secrete IFNγ when stimulated with polyp antigens and were inefficient in T-helper-1 (TH1) commitment. By contrast, the TH17 commitment was unaffected. These findings were validated using mice whose T cells overexpress IL10. In these mice, we observed high intra-polyp cytotoxic activity and attenuation of polyposis. Thus, expression of IL10 by T cells is protective and required for immune surveillance in the small intestine., (©2015 American Association for Cancer Research.)
- Published
- 2015
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26. IL-10-producing intestinal macrophages prevent excessive antibacterial innate immunity by limiting IL-23 synthesis.
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Krause P, Morris V, Greenbaum JA, Park Y, Bjoerheden U, Mikulski Z, Muffley T, Shui JW, Kim G, Cheroutre H, Liu YC, Peters B, Kronenberg M, and Murai M
- Subjects
- Animals, Bone Marrow Cells physiology, Caspase 1 genetics, Caspase 1 metabolism, Female, Gene Expression Regulation physiology, Interleukin-10 genetics, Interleukin-1beta genetics, Interleukin-1beta metabolism, Interleukin-23 genetics, Male, Mice, Mice, Inbred Strains, Mice, Knockout, Osmotic Pressure, Sodium Chloride, Dietary administration & dosage, Sodium Chloride, Dietary toxicity, Stress, Physiological, Th17 Cells, Immunity, Innate physiology, Interleukin-10 metabolism, Interleukin-23 metabolism, Intestines cytology, Macrophages metabolism
- Abstract
Innate immune responses are regulated in the intestine to prevent excessive inflammation. Here we show that a subset of mouse colonic macrophages constitutively produce the anti-inflammatory cytokine IL-10. In mice infected with Citrobacter rodentium, a model for enteropathogenic Escherichia coli infection in humans, these macrophages are required to prevent intestinal pathology. IL-23 is significantly increased in infected mice with a myeloid cell-specific deletion of IL-10, and the addition of IL-10 reduces IL-23 production by intestinal macrophages. Furthermore, blockade of IL-23 leads to reduced mortality in the context of macrophage IL-10 deficiency. Transcriptome and other analyses indicate that IL-10-expressing macrophages receive an autocrine IL-10 signal. Interestingly, only transfer of the IL-10 positive macrophages could rescue IL-10-deficient infected mice. Therefore, these data indicate a pivotal role for intestinal macrophages that constitutively produce IL-10, in controlling excessive innate immune activation and preventing tissue damage after an acute bacterial infection.
- Published
- 2015
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27. αβT cell receptors expressed by CD4(-)CD8αβ(-) intraepithelial T cells drive their fate into a unique lineage with unusual MHC reactivities.
- Author
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Mayans S, Stepniak D, Palida S, Larange A, Dreux J, Arlian B, Shinnakasu R, Kronenberg M, Cheroutre H, and Lambolez F
- Subjects
- Animals, Cell Differentiation immunology, Histocompatibility Antigens Class I immunology, Histocompatibility Antigens Class II immunology, Immunologic Surveillance immunology, Lymphocyte Activation immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Cell Lineage immunology, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, alpha-beta immunology
- Abstract
Coreceptor CD4 and CD8αβ double-negative (DN) TCRαβ(+) intraepithelial T cells, although numerous, have been greatly overlooked and their contribution to the immune response is not known. Here we used T cell receptor (TCR) sequencing of single cells combined with retrogenic expression of TCRs to study the fate and the major histocompatibility complex (MHC) restriction of DN TCRαβ(+) intraepithelial T cells. The data show that commitment of thymic precursors to the DN TCRαβ(+) lineage is imprinted by their TCR specificity. Moreover, the TCRs they express display a diverse and unusual pattern of MHC restriction that is nonoverlapping with that of CD4(+) or CD8αβ(+) T cells, indicating that they sense antigens that are not recognized by the conventional T cell subsets. The new insights indicate that DN TCRαβ(+) T cells form a third lineage of TCRαβ T lymphocytes expressing a variable TCR repertoire, which serve nonredundant immune functions., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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28. Negative selection of self-reactive chicken B cells requires B cell receptor signaling and is independent of the bursal microenvironment.
- Author
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Davani D, Pancer Z, Cheroutre H, and Ratcliffe MJ
- Subjects
- Animals, Autoantigens metabolism, Avian Proteins genetics, Avian Proteins metabolism, B-Lymphocytes metabolism, Bursa of Fabricius cytology, Bursa of Fabricius immunology, Bursa of Fabricius metabolism, CD79 Antigens genetics, CD79 Antigens immunology, CD79 Antigens metabolism, CD8 Antigens genetics, CD8 Antigens immunology, CD8 Antigens metabolism, Cell Line, Tumor, Cells, Cultured, Chick Embryo, Chickens, Fibroblasts cytology, Fibroblasts immunology, Fibroblasts metabolism, Flow Cytometry, Immunoglobulin M genetics, Immunoglobulin M immunology, Immunoglobulin M metabolism, Lampreys genetics, Lampreys immunology, Mice, Muramidase immunology, Protein Binding immunology, Receptors, Antigen genetics, Receptors, Antigen immunology, Receptors, Antigen metabolism, Receptors, Antigen, B-Cell genetics, Receptors, Antigen, B-Cell metabolism, Receptors, Fc genetics, Receptors, Fc immunology, Receptors, Fc metabolism, Autoantigens immunology, Avian Proteins immunology, B-Lymphocytes immunology, Cellular Microenvironment immunology, Receptors, Antigen, B-Cell immunology, Signal Transduction immunology
- Abstract
Although the negative selection of self-reactive B cells in the bone marrow of mammals has been clearly demonstrated, it remains unclear in models of gut-associated B cell lymphopoiesis, such as that of the chicken (Gallus gallus). We have generated chicken surface IgM-related receptors in which the diversity region of the lamprey variable lymphocyte receptor (VLR) has been fused to the C region of chicken surface IgM (Tμ). Expression of a VLR:Tμ receptor with specificity for PE supported normal development of B cells, whereas a VLR:Tμ receptor specific to hen egg lysozyme (a self-antigen with respect to chicken B cells) induced, in vivo, complete deletion of VLR(HEL)Tμ-expressing B cells. In ovo i.v. injection of PE resulted in deletion of VLR(PE)Tμ-expressing Β cells in the embryo spleen, demonstrating that negative selection was independent of the bursal microenvironment. Although chickens transduced with a murine CD8α:chicken Igα fusion protein contained B cells expressing mCD8α:chIgα, cotransfection of the mCD8α:chIgα construct, together with thymus leukemia Ag (a natural ligand for mCD8α), resulted in reduced levels of mCD8α:chIgα-expressing B cells in inverse proportion to the levels of thymus leukemia Ag-expressing cells. Deletion of mCD8α:chIgα-expressing cells was specific for B cells and required active signaling downstream of the mCD8α:chIgα receptor. Ag-mediated negative selection of developing chicken B cells can therefore occur independently of the bursal microenvironment and is dependent on signaling downstream of the BCR.
- Published
- 2014
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29. Themis sets the signal threshold for positive and negative selection in T-cell development.
- Author
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Fu G, Casas J, Rigaud S, Rybakin V, Lambolez F, Brzostek J, Hoerter JA, Paster W, Acuto O, Cheroutre H, Sauer K, and Gascoigne NR
- Subjects
- Animals, Apoptosis, Autoantigens immunology, Calcium Signaling, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases metabolism, Intercellular Signaling Peptides and Proteins, Ligands, Mice, Mice, Inbred C57BL, Protein Tyrosine Phosphatase, Non-Receptor Type 6 metabolism, Proteins genetics, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes immunology, Thymocytes immunology, Proteins metabolism, Receptors, Antigen, T-Cell immunology, Signal Transduction immunology, T-Lymphocytes cytology, T-Lymphocytes metabolism, Thymocytes cytology, Thymocytes metabolism
- Abstract
Development of a self-tolerant T-cell receptor (TCR) repertoire with the potential to recognize the universe of infectious agents depends on proper regulation of TCR signalling. The repertoire is whittled down during T-cell development in the thymus by the ability of quasi-randomly generated TCRs to interact with self-peptides presented by major histocompatibility complex (MHC) proteins. Low-affinity TCR interactions with self-MHC proteins generate weak signals that initiate 'positive selection', causing maturation of CD4- or CD8αβ-expressing 'single-positive' thymocytes from CD4(+)CD8αβ(+) 'double-positive' precursors. These develop into mature naive T cells of the secondary lymphoid organs. TCR interaction with high-affinity agonist self-ligands results in 'negative selection' by activation-induced apoptosis or 'agonist selection' of functionally differentiated self-antigen-experienced T cells. Here we show that positive selection is enabled by the ability of the T-cell-specific protein Themis to specifically attenuate TCR signal strength via SHP1 recruitment and activation in response to low- but not high-affinity TCR engagement. Themis acts as an analog-to-digital converter translating graded TCR affinity into clear-cut selection outcome. By dampening mild TCR signals Themis increases the affinity threshold for activation, enabling positive selection of T cells with a naive phenotype in response to low-affinity self-antigens.
- Published
- 2013
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30. CD4 CTL: living up to the challenge.
- Author
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Cheroutre H and Husain MM
- Subjects
- Animals, Autoimmune Diseases genetics, Autoimmune Diseases immunology, Autoimmune Diseases metabolism, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes metabolism, Cell Differentiation immunology, Cell Lineage immunology, Gene Expression Regulation, Humans, Inflammation genetics, Inflammation immunology, Inflammation metabolism, Lymphocyte Activation immunology, Lymphoid Tissue immunology, Lymphoid Tissue metabolism, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets metabolism, T-Lymphocytes, Helper-Inducer cytology, T-Lymphocytes, Helper-Inducer immunology, T-Lymphocytes, Helper-Inducer metabolism, Thymus Gland immunology, Thymus Gland metabolism, Transcription Factors metabolism, Transcription, Genetic, CD4-Positive T-Lymphocytes immunology, Cytotoxicity, Immunologic, T-Lymphocyte Subsets immunology
- Abstract
During thymic development, thymocytes expressing a T cell receptor consisting of an alpha and beta chain (TCRαβ), commit to either the cytotoxic- or T helper-lineage fate. This lineage dichotomy is controlled by key transcription factors, including the T helper (Th) lineage master regulator, the Th-inducing BTB/POZ domain-containing Kruppel-like zinc-finger transcription factor, ThPOK, (formally cKrox or Zfp67; encoded by Zbtb7b), which suppresses the cytolytic program in major histocompatibility complex (MHC) class II-restricted CD4(+) thymocytes and the Runt related transcription factor 3 (Runx3), which counteracts ThPOK in MHC class I restricted precursor cells and promotes the lineage commitment of CD8αβ(+) cytolytic T lymphocytes (CTL). ThPOK continues to repress the CTL gene program in mature CD4(+) T cells, even as they differentiate into effector Th cell subsets. The Th cell fate however is not fixed and two recent studies showed that mature, antigen-stimulated CD4(+) T cells have the flexibility to terminate the expression of ThPOK and functionally reprogram to cytotoxic effector cells. This unexpected plasticity of CD4(+) T cells results in the post-thymic termination of the Th lineage fate and the functional differentiation of distinct MHC class II-restricted CD4(+) CTL. The recognition of CD4 CTL as a defined separate subset of effector cells and the identification of the mechanisms and factors that drive their reprogramming finally create new opportunities to explore the physiological relevance of these effector cells in vivo and to determine their pivotal roles in both, protective immunity as well as in immune-related pathology., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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31. BTLA interaction with HVEM expressed on CD8(+) T cells promotes survival and memory generation in response to a bacterial infection.
- Author
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Steinberg MW, Huang Y, Wang-Zhu Y, Ware CF, Cheroutre H, and Kronenberg M
- Subjects
- Animals, Cells, Cultured, Flow Cytometry, Fluorescent Antibody Technique, Listeria monocytogenes immunology, Listeria monocytogenes pathogenicity, Mice, Mice, Inbred C57BL, Protein Binding, CD8-Positive T-Lymphocytes metabolism, Receptors, Immunologic metabolism, Receptors, Tumor Necrosis Factor, Member 14 metabolism
- Abstract
The B and T lymphocyte attenuator (BTLA) is an Ig super family member that binds to the herpes virus entry mediator (HVEM), a TNF receptor super family (TNFRSF) member. Engagement of BTLA by HVEM triggers inhibitory signals, although recent evidence indicates that BTLA also may act as an activating ligand for HVEM. In this study, we reveal a novel role for the BTLA-HVEM pathway in promoting the survival of activated CD8(+) T cells in the response to an oral microbial infection. Our data show that both BTLA- and HVEM-deficient mice infected with Listeria monocytogenes had significantly reduced numbers of primary effector and memory CD8(+) T cells, despite normal proliferation and expansion compared to controls. In addition, blockade of the BTLA-HVEM interaction early in the response led to significantly reduced numbers of antigen-specific CD8(+) T cells. HVEM expression on the CD8(+) T cells as well as BTLA expression on a cell type other than CD8(+) T lymphocytes, was required. Collectively, our data demonstrate that the function of the BTLA-HVEM pathway is not limited to inhibitory signaling in T lymphocytes, and instead, that BTLA can provide crucial, HVEM-dependent signals that promote survival of antigen activated CD8(+) T cell during bacterial infection.
- Published
- 2013
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32. T cell-derived protein S engages TAM receptor signaling in dendritic cells to control the magnitude of the immune response.
- Author
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Carrera Silva EA, Chan PY, Joannas L, Errasti AE, Gagliani N, Bosurgi L, Jabbour M, Perry A, Smith-Chakmakova F, Mucida D, Cheroutre H, Burstyn-Cohen T, Leighton JA, Lemke G, Ghosh S, and Rothlin CV
- Subjects
- Animals, Cells, Cultured, Colitis genetics, Colitis immunology, Cytokines immunology, Cytokines metabolism, Dendritic Cells metabolism, Flow Cytometry, Gene Expression immunology, Humans, Immunoblotting, Lymphocyte Activation immunology, Mice, Mice, Knockout, Mice, Transgenic, Protein S genetics, Protein S metabolism, Receptor Protein-Tyrosine Kinases metabolism, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes metabolism, Adaptive Immunity immunology, Dendritic Cells immunology, Protein S immunology, Receptor Protein-Tyrosine Kinases immunology, Signal Transduction immunology, T-Lymphocytes immunology
- Abstract
Dendritic cell (DC) activation is essential for the induction of immune defense against pathogens, yet needs to be tightly controlled to avoid chronic inflammation and exaggerated immune responses. Here, we identify a mechanism of immune homeostasis by which adaptive immunity, once triggered, tempers DC activation and prevents overreactive immune responses. T cells, once activated, produced Protein S (Pros1) that signaled through TAM receptor tyrosine kinases in DCs to limit the magnitude of DC activation. Genetic ablation of Pros1 in mouse T cells led to increased expression of costimulatory molecules and cytokines in DCs and enhanced immune responses to T cell-dependent antigens, as well as increased colitis. Additionally, PROS1 was expressed in activated human T cells, and its ability to regulate DC activation was conserved. Our results identify a heretofore unrecognized, homeostatic negative feedback mechanism at the interface of adaptive and innate immunity that maintains the physiological magnitude of the immune response., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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33. Transcriptional reprogramming of mature CD4⁺ helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes.
- Author
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Mucida D, Husain MM, Muroi S, van Wijk F, Shinnakasu R, Naoe Y, Reis BS, Huang Y, Lambolez F, Docherty M, Attinger A, Shui JW, Kim G, Lena CJ, Sakaguchi S, Miyamoto C, Wang P, Atarashi K, Park Y, Nakayama T, Honda K, Ellmeier W, Kronenberg M, Taniuchi I, and Cheroutre H
- Subjects
- Animals, Cell Differentiation, Cell Lineage, Citrobacter rodentium immunology, Histocompatibility Antigens Class II immunology, Homeodomain Proteins genetics, Interleukin-7 genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Cytotoxic cytology, T-Lymphocytes, Cytotoxic metabolism, T-Lymphocytes, Helper-Inducer cytology, T-Lymphocytes, Helper-Inducer metabolism, Thymocytes metabolism, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Helper-Inducer immunology, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
TCRαβ thymocytes differentiate into either CD8αβ(+) cytotoxic T lymphocytes or CD4(+) helper T cells. This functional dichotomy is controlled by key transcription factors, including the helper T cell master regulator ThPOK, which suppresses the cytolytic program in major histocompatibility complex (MHC) class II-restricted CD4(+) thymocytes. ThPOK continues to repress genes of the CD8 lineage in mature CD4(+) T cells, even as they differentiate into effector helper T cell subsets. Here we found that the helper T cell fate was not fixed and that mature, antigen-stimulated CD4(+) T cells terminated expression of the gene encoding ThPOK and reactivated genes of the CD8 lineage. This unexpected plasticity resulted in the post-thymic termination of the helper T cell program and the functional differentiation of distinct MHC class II-restricted CD4(+) cytotoxic T lymphocytes.
- Published
- 2013
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34. A novel role for IL-27 in mediating the survival of activated mouse CD4 T lymphocytes.
- Author
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Kim G, Shinnakasu R, Saris CJ, Cheroutre H, and Kronenberg M
- Subjects
- Animals, CD4-Positive T-Lymphocytes transplantation, Cell Death genetics, Cell Death immunology, Cell Differentiation genetics, Cell Differentiation immunology, Cell Proliferation, Cell Survival genetics, Cell Survival immunology, Colitis immunology, Colitis pathology, Colitis prevention & control, Homeostasis genetics, Homeostasis immunology, Interleukins deficiency, Interleukins genetics, Lymphocyte Activation genetics, Mice, Mice, Knockout, Mice, Transgenic, Signal Transduction genetics, Signal Transduction immunology, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, Interleukins physiology, Lymphocyte Activation immunology
- Abstract
IL-27, an IL-12 family cytokine, has pleiotropic functions in the differentiation and expansion of CD4(+) T cell subsets. In this study, we discovered a novel function of IL-27. CD4(+)CD45RB(high) T cells from mice deficient for the α-chain of IL-27 receptor failed to induce colitis in Rag(-/-) recipients, because of an inability of activated donor cells to survive. Interestingly, IL-27 was indispensable for the prevention of colitis by regulatory T cells, also because of a defect in long-term cell survival. IL-27 affected the survival of activated T lymphocytes, rather than promoting cell proliferation, by inhibiting Fas-mediated activation-induced T cell death, acting through the STAT3 signaling pathway. The addition of IL-27 during activation resulted in an increased cell number, which was correlated with decreased activation of both caspases 3 and 8. This prosurvival effect was attributed to downregulation of FasL and to the induction of the antiapoptotic protein cFLIP. Although activation induced cell death is an important mechanism for the maintenance of immunological homeostasis, protection of lymphocytes from excessive cell death is essential for effective immunity. Our data indicate that IL-27 has a crucial role in the inhibition of activation-induced cell death, thereby permitting Ag-driven T cell expansion.
- Published
- 2013
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35. Crosstalk between adaptive and innate immune cells leads to high quality immune protection at the mucosal borders.
- Author
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Cheroutre H and Huang Y
- Subjects
- Animals, Antigen-Presenting Cells cytology, Antigen-Presenting Cells immunology, CD8 Antigens genetics, CD8 Antigens immunology, CD8-Positive T-Lymphocytes cytology, Epithelial Cells cytology, Epithelial Cells immunology, Gene Expression, Humans, Intestinal Mucosa cytology, Intestinal Mucosa immunology, Lymphoid Tissue cytology, Lymphoid Tissue immunology, Membrane Glycoproteins genetics, Membrane Glycoproteins immunology, T-Lymphocyte Subsets cytology, Adaptive Immunity, CD8-Positive T-Lymphocytes immunology, Immunity, Innate, Immunity, Mucosal, Immunologic Memory, T-Lymphocyte Subsets immunology
- Abstract
Mucosal effector memory CD8 T cells are located at the epithelium and have a heightened and immediate effector function. By contrast, central memory T cells reside within lymphoid tissues and require proliferation and differentiation to become effector cells that migrate to epithelial surfaces. The accumulation of effector memory T cells at the pathogen entry site(s) is essential for protective immunity, but the mechanisms that drive the differentiation of memory cell subsets are poorly understood. We recently showed that CD8αα, induced selectively on the most highly activated primary CD8αβ T cells, together with its ligand, the thymic leukemia (TL) antigen, induced on mucosal antigen-presenting cells and constitutively expressed on intestinal epithelial cells (IEC), serve as key components to mediate the selective accumulation of the fittest effector cells to form mucosal effector memory T cells. Therefore, the generation of mucosal effector memory is controlled by an innate-adaptive crosstalk that provides for host defense at the body's largest interface.
- Published
- 2013
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36. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth.
- Author
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Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B, Jauch D, Taniguchi K, Yu GY, Osterreicher CH, Hung KE, Datz C, Feng Y, Fearon ER, Oukka M, Tessarollo L, Coppola V, Yarovinsky F, Cheroutre H, Eckmann L, Trinchieri G, and Karin M
- Subjects
- Adenoma genetics, Adenoma immunology, Animals, Bacteria metabolism, Bacteria pathogenicity, Cell Division, Colitis complications, Colorectal Neoplasms genetics, Colorectal Neoplasms immunology, Disease Models, Animal, Disease-Free Survival, Genes, APC, Humans, Inflammation genetics, Inflammation immunology, Inflammation microbiology, Inflammation pathology, Interleukin-17 genetics, Interleukin-23 deficiency, Interleukin-23 genetics, Mice, Mice, Inbred C57BL, Myeloid Cells immunology, Myeloid Cells metabolism, Myeloid Differentiation Factor 88 immunology, Myeloid Differentiation Factor 88 metabolism, Signal Transduction, Toll-Like Receptors immunology, Toll-Like Receptors metabolism, Tumor Microenvironment, beta Catenin metabolism, Adenoma microbiology, Adenoma pathology, Cell Transformation, Neoplastic pathology, Colorectal Neoplasms microbiology, Colorectal Neoplasms pathology, Interleukin-17 immunology, Interleukin-23 immunology
- Abstract
Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of β-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses. Curiously, however, 'inflammatory signature' genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates, referred to as 'tumour-elicited inflammation'. Although infiltrating CD4(+) T(H)1 cells and CD8(+) cytotoxic T cells constitute a positive prognostic sign in colorectal cancer, myeloid cells and T-helper interleukin (IL)-17-producing (T(H)17) cells promote tumorigenesis, and a 'T(H)17 expression signature' in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL-23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth.
- Published
- 2012
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37. Cutting edge: 4-1BB controls regulatory activity in dendritic cells through promoting optimal expression of retinal dehydrogenase.
- Author
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Lee SW, Park Y, Eun SY, Madireddi S, Cheroutre H, and Croft M
- Subjects
- Animals, Cells, Cultured, Dendritic Cells enzymology, Glyceraldehyde-3-Phosphate Dehydrogenases genetics, Intestinal Mucosa enzymology, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Lymph Nodes cytology, Lymph Nodes immunology, Lymph Nodes metabolism, Mesentery cytology, Mesentery immunology, Mesentery metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Retinal Pigment Epithelium enzymology, Spleen cytology, Spleen immunology, Spleen metabolism, Tumor Necrosis Factor Receptor Superfamily, Member 9 deficiency, Tumor Necrosis Factor Receptor Superfamily, Member 9 genetics, Dendritic Cells immunology, Dendritic Cells metabolism, Gene Expression Regulation, Enzymologic genetics, Glyceraldehyde-3-Phosphate Dehydrogenases biosynthesis, Retinal Pigment Epithelium immunology, Retinal Pigment Epithelium metabolism, Tumor Necrosis Factor Receptor Superfamily, Member 9 physiology
- Abstract
Dendritic cells (DC) in the gut promote immune tolerance by expressing retinal dehydrogenase (RALDH), an enzyme that promotes retinoic acid, which aids differentiation of Foxp3+ inducible regulatory T cells (iTreg) in the intestinal mucosa. How RALDH expression is regulated is unclear. We found that 4-1BB (CD137), a member of the TNFR family, together with CD103, marked mesenteric lymph node DC with the highest level of RALDH activity, and ligation of 4-1BB maintained RALDH expression in these gut DC. Moreover, 4-1BB signals synergized with those through TLR2 or GM-CSFR to promote RALDH activity in undifferentiated DC. Correspondingly, 4-1BB-deficient mice were impaired in their ability to generate iTreg in the GALT when exposed to oral Ag, and 4-1BB-deficient mesenteric lymph node DC displayed weak RALDH activity and were poor at promoting iTreg development. Thus, our data demonstrate a novel activity of 4-1BB in controlling RALDH expression and the regulatory activity of DC.
- Published
- 2012
- Full Text
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38. HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria.
- Author
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Shui JW, Larange A, Kim G, Vela JL, Zahner S, Cheroutre H, and Kronenberg M
- Subjects
- Animals, Antigens, CD immunology, Antigens, CD metabolism, Bacterial Load, Cell Line, Disease Models, Animal, Enterobacteriaceae Infections immunology, Enterobacteriaceae Infections microbiology, Enteropathogenic Escherichia coli, Epithelial Cells immunology, Epithelial Cells metabolism, Escherichia coli Infections, GPI-Linked Proteins immunology, GPI-Linked Proteins metabolism, Intestines immunology, Intestines microbiology, Ligands, Lung immunology, Lung microbiology, Lymphocytes immunology, Lymphocytes metabolism, Mice, Mice, Inbred C57BL, Mucous Membrane metabolism, Pneumococcal Infections immunology, Pneumococcal Infections microbiology, Protein Serine-Threonine Kinases metabolism, Receptors, Immunologic immunology, Receptors, Immunologic metabolism, Receptors, Tumor Necrosis Factor, Member 14 deficiency, Receptors, Tumor Necrosis Factor, Member 14 genetics, Receptors, Tumor Necrosis Factor, Member 14 immunology, STAT3 Transcription Factor metabolism, Streptococcus pneumoniae immunology, Survival Rate, NF-kappaB-Inducing Kinase, Citrobacter rodentium immunology, Citrobacter rodentium pathogenicity, Immunity, Mucosal immunology, Mucous Membrane immunology, Mucous Membrane microbiology, Receptors, Tumor Necrosis Factor, Member 14 metabolism, Signal Transduction
- Abstract
The herpes virus entry mediator (HVEM), a member of the tumour-necrosis factor receptor family, has diverse functions, augmenting or inhibiting the immune response. HVEM was recently reported as a colitis risk locus in patients, and in a mouse model of colitis we demonstrated an anti-inflammatory role for HVEM, but its mechanism of action in the mucosal immune system was unknown. Here we report an important role for epithelial HVEM in innate mucosal defence against pathogenic bacteria. HVEM enhances immune responses by NF-κB-inducing kinase-dependent Stat3 activation, which promotes the epithelial expression of genes important for immunity. During intestinal Citrobacter rodentium infection, a mouse model for enteropathogenic Escherichia coli infection, Hvem−/− mice showed decreased Stat3 activation, impaired responses in the colon, higher bacterial burdens and increased mortality. We identified the immunoglobulin superfamily molecule CD160 (refs 7 and 8), expressed predominantly by innate-like intraepithelial lymphocytes, as the ligand engaging epithelial HVEM for host protection. Likewise, in pulmonary Streptococcus pneumoniae infection, HVEM is also required for host defence. Our results pinpoint HVEM as an important orchestrator of mucosal immunity, integrating signals from innate lymphocytes to induce optimal epithelial Stat3 activation, which indicates that targeting HVEM with agonists could improve host defence.
- Published
- 2012
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39. Protein kinase C η is required for T cell activation and homeostatic proliferation.
- Author
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Fu G, Hu J, Niederberger-Magnenat N, Rybakin V, Casas J, Yachi PP, Feldstein S, Ma B, Hoerter JA, Ampudia J, Rigaud S, Lambolez F, Gavin AL, Sauer K, Cheroutre H, and Gascoigne NR
- Subjects
- Animals, Base Sequence, CD4-CD8 Ratio, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes enzymology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes enzymology, CD8-Positive T-Lymphocytes immunology, Calcium Signaling, Cell Proliferation, Homeostasis, Immunologic Memory physiology, Immunological Synapses enzymology, Isoenzymes deficiency, Isoenzymes genetics, Isoenzymes immunology, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B metabolism, Phenotype, Protein Kinase C deficiency, Protein Kinase C genetics, Protein Kinase C-theta, RNA, Messenger genetics, RNA, Messenger metabolism, Signal Transduction immunology, T-Lymphocytes cytology, Protein Kinase C immunology, T-Lymphocytes enzymology, T-Lymphocytes immunology
- Abstract
Protein kinase C η (PKCη) is abundant in T cells and is recruited to the immunological synapse that is formed between a T cell and an antigen-presenting cell; however, its function in T cells is unknown. We showed that PKCη was required for the activation of mature CD8+ T cells through the T cell receptor. Compared with wild-type T cells, PKCη-/- T cells showed poor proliferation in response to antigen stimulation, a trait shared with T cells deficient in PKCθ, which is the most abundant PKC isoform in T cells and was thought to be the only PKC isoform with a specific role in T cell activation. In contrast, only PKCη-deficient T cells showed defective homeostatic proliferation, which requires self-antigen recognition. PKCη was dispensable for thymocyte development; however, thymocytes from mice doubly deficient in PKCη and PKCθ exhibited poor development, indicating some redundancy between the PKC isoforms. Deficiency in PKCη or PKCθ had opposing effects on the relative numbers of CD4+ and CD8+ T cells. PKCη-/- mice had a higher ratio of CD4+ to CD8+ T cells compared to that of wild-type mice, whereas PKCθ-/- mice had a lower ratio. Mice deficient in both isoforms exhibited normal cell ratios. Together, these data suggest that PKCη shares some redundant roles with PKCθ in T cell biology and also performs nonredundant functions that are required for T cell homeostasis and activation.
- Published
- 2011
- Full Text
- View/download PDF
40. Mucosal memory CD8⁺ T cells are selected in the periphery by an MHC class I molecule.
- Author
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Huang Y, Park Y, Wang-Zhu Y, Larange A, Arens R, Bernardo I, Olivares-Villagómez D, Herndler-Brandstetter D, Abraham N, Grubeck-Loebenstein B, Schoenberger SP, Van Kaer L, Kronenberg M, Teitell MA, and Cheroutre H
- Subjects
- Animals, Antigens immunology, Antigens metabolism, CD8 Antigens metabolism, Cell Differentiation, Clonal Selection, Antigen-Mediated, Dendritic Cells immunology, Dendritic Cells pathology, Immunity, Mucosal genetics, Immunologic Memory genetics, Lymphocyte Activation genetics, Membrane Glycoproteins genetics, Membrane Glycoproteins immunology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Precursor Cells, T-Lymphoid immunology, Precursor Cells, T-Lymphoid pathology, T-Lymphocytes immunology, T-Lymphocytes pathology, Transgenes genetics, Dendritic Cells metabolism, Listeriosis immunology, Membrane Glycoproteins metabolism, Precursor Cells, T-Lymphoid metabolism, T-Lymphocytes metabolism
- Abstract
The presence of immune memory at pathogen-entry sites is a prerequisite for protection. Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood. Here we show that the nonclassical major histocompatibility complex (MHC) class I molecule thymus leukemia antigen (TL), induced on dendritic cells interacting with CD8αα on activated CD8αβ(+) T cells, mediated affinity-based selection of memory precursor cells. Furthermore, constitutive expression of TL on epithelial cells led to continued selection of mature CD8αβ(+) memory T cells. The memory process driven by TL and CD8αα was essential for the generation of CD8αβ(+) memory T cells in the intestine and the accumulation of highly antigen-sensitive CD8αβ(+) memory T cells that form the first line of defense at the largest entry port for pathogens.
- Published
- 2011
- Full Text
- View/download PDF
41. Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation.
- Author
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Guma M, Stepniak D, Shaked H, Spehlmann ME, Shenouda S, Cheroutre H, Vicente-Suarez I, Eckmann L, Kagnoff MF, and Karin M
- Subjects
- Animals, Cytokines biosynthesis, Cytokines genetics, Cytokines immunology, Enzyme Activation genetics, Enzyme Activation immunology, Gene Expression genetics, Gene Expression immunology, I-kappa B Kinase genetics, I-kappa B Kinase immunology, I-kappa B Kinase metabolism, Inflammation genetics, Inflammation immunology, Inflammation metabolism, Intestinal Mucosa metabolism, MAP Kinase Signaling System genetics, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase Kinases genetics, Mitogen-Activated Protein Kinase Kinases metabolism, NF-kappa B genetics, NF-kappa B metabolism, Intestinal Mucosa immunology, MAP Kinase Signaling System immunology, Mitogen-Activated Protein Kinase Kinases immunology, NF-kappa B immunology
- Abstract
Nuclear factor (NF)-κB, activated by IκB kinase (IKK), is a key regulator of inflammation, innate immunity, and tissue integrity. NF-κB and one of its main activators and transcriptional targets, tumor necrosis factor (TNF), are up-regulated in many inflammatory diseases that are accompanied by tissue destruction. The etiology of many inflammatory diseases is poorly understood, but often depends on genetic factors and environmental triggers that affect NF-κB and related pathways. It is unknown, however, whether persistent NF-κB activation is sufficient for driving symptomatic chronic inflammation and tissue damage. To address this question, we generated IKKβ(EE)(IEC) mice, which express a constitutively active form of IKKβ in intestinal epithelial cell (IECs). IKKβ(EE)(IEC) mice exhibit NF-κB activation in IECs and express copious amounts of inflammatory chemokines, but only small amounts of TNF. Although IKKβ(EE)(IEC) mice exhibit inflammatory cell infiltration in the lamina propria (LP) of their small intestine, they do not manifest tissue damage. Yet, upon challenge with relatively mild immune and microbial stimuli, IKKβ(EE)(IEC) mice succumb to destructive acute inflammation accompanied by enterocyte apoptosis, intestinal barrier disruption, and bacterial translocation. Inflammation is driven by massive TNF production, which requires additional activation of p38 and extracellular-signal-regulated kinase mitogen-activated protein kinases (MAPKs)., (© 2011 Guma et al.)
- Published
- 2011
- Full Text
- View/download PDF
42. The light and dark sides of intestinal intraepithelial lymphocytes.
- Author
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Cheroutre H, Lambolez F, and Mucida D
- Subjects
- Animals, Cell Differentiation immunology, Cell Movement immunology, Humans, Inflammation immunology, Lymphocytes cytology, Models, Immunological, Epithelium immunology, Intestinal Mucosa immunology, Intestines immunology, Lymphocytes immunology
- Abstract
The intraepithelial lymphocytes (IELs) that reside within the epithelium of the intestine form one of the main branches of the immune system. As IELs are located at this critical interface between the core of the body and the outside environment, they must balance protective immunity with an ability to safeguard the integrity of the epithelial barrier: failure to do so would compromise homeostasis of the organism. In this Review, we address how the unique development and functions of intestinal IELs allow them to achieve this balance.
- Published
- 2011
- Full Text
- View/download PDF
43. Hepatic stellate cells function as regulatory bystanders.
- Author
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Ichikawa S, Mucida D, Tyznik AJ, Kronenberg M, and Cheroutre H
- Subjects
- Animals, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes metabolism, Cells, Cultured, Dendritic Cells immunology, Dendritic Cells metabolism, Flow Cytometry, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Galactosylceramides metabolism, Genes, MHC Class II, Interferon-gamma immunology, Killer Cells, Natural immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Polymerase Chain Reaction, Receptors, Antigen, T-Cell, Th17 Cells cytology, Th17 Cells immunology, Th17 Cells metabolism, CD4-Positive T-Lymphocytes immunology, Hepatic Stellate Cells immunology, Hepatic Stellate Cells metabolism, Tretinoin metabolism
- Abstract
Regulatory T cells (Tregs) contribute significantly to the tolerogenic nature of the liver. The mechanisms, however, underlying liver-associated Treg induction are still elusive. We recently identified the vitamin A metabolite, retinoic acid (RA), as a key controller that promotes TGF-β-dependent Foxp3(+) Treg induction but inhibits TGF-β-driven Th17 differentiation. To investigate whether the RA producing hepatic stellate cells (HSC) are part of the liver tolerance mechanism, we investigated the ability of HSC to function as regulatory APC. Different from previous reports, we found that highly purified HSC did not express costimulatory molecules and only upregulated MHC class II after in vitro culture in the presence of exogenous IFN-γ. Consistent with an insufficient APC function, HSC failed to stimulate naive OT-II TCR transgenic CD4(+) T cells and only moderately stimulated α-galactosylceramide-primed invariant NKT cells. In contrast, HSC functioned as regulatory bystanders and promoted enhanced Foxp3 induction by OT-II TCR transgenic T cells primed by spleen dendritic cells, whereas they greatly inhibited the Th17 differentiation. Furthermore, the regulatory bystander capacity of the HSC was completely dependent on their ability to produce RA. Our data thus suggest that HSC can function as regulatory bystanders, and therefore, by promoting Tregs and suppressing Th17 differentiation, they might represent key players in the mechanism that drives liver-induced tolerance.
- Published
- 2011
- Full Text
- View/download PDF
44. Mucosal T cells in gut homeostasis and inflammation.
- Author
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van Wijk F and Cheroutre H
- Subjects
- Homeostasis immunology, Humans, Immunity, Mucosal immunology, Models, Immunological, Gastrointestinal Tract immunology, Inflammation immunology, Intestinal Mucosa immunology, T-Lymphocytes immunology
- Abstract
The antigen-rich environment of the gut interacts with a highly integrated and specialized mucosal immune system that has the challenging task of preventing invasion and the systemic spread of microbes, while avoiding excessive or unnecessary immune responses to innocuous antigens. Disruption of the mucosal barrier and/or defects in gut immune regulatory networks may lead to chronic intestinal inflammation as seen in inflammatory bowel disease. The T-cell populations of the intestine play a critical role in controlling intestinal homeostasis, and their unique phenotypes and diversities reflect the sophisticated mechanisms that have evolved to maintain the delicate balance between immune activation and tolerance at mucosal sites. In this article, we will discuss the specialized properties of mucosal T cells in the context of immune homeostasis and inflammation.
- Published
- 2010
- Full Text
- View/download PDF
45. The 2010 Midwinter Conference of Immunologists at Asilomar.
- Author
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Schoenberger SP, Cheroutre H, Uittenbogaart C, and Marshak-Rothstein A
- Subjects
- Adaptive Immunity, Allergy and Immunology education, Animals, California, Gene Expression Regulation immunology, Humans, Immune Tolerance, Immunity, Innate, Immunosuppression Therapy, Mice, Allergy and Immunology trends, Autoimmune Diseases immunology, Receptors, Pattern Recognition immunology, Transcription Factors immunology
- Published
- 2010
- Full Text
- View/download PDF
46. The many face-lifts of CD4 T helper cells.
- Author
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Mucida D and Cheroutre H
- Subjects
- Animals, Humans, Cell Differentiation immunology, Cell Lineage immunology, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets immunology, T-Lymphocytes, Helper-Inducer cytology, T-Lymphocytes, Helper-Inducer immunology
- Abstract
Recent advances in stem cell research have redefined previous concepts of hematopoietic hierarchy, lineage commitment, and cell fate. The immune system is comprised of several well-defined cell lineages of which many exhibit high levels of plasticity or capacity in changing their phenotype. The CD4 T helper cells provide a peculiar example of apparently defined cell subsets, at times described as lineages, but also highly sensitive to tissue environmental cues that may change their fate. The classical Th1/Th2 CD4 T cell differentiation referred to for many years as the main CD4 T cell fate dichotomy and the later additions of CD4 helper T cell variants, such as T helper 17 (Th17) and induced regulatory T cells (iTreg), have added complexity but also doubts on the accuracy of defining CD4 T cell subsets as fixed T cell lineages., (Copyright © 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
47. HIV vaccination: turning the spotlight on effector memory T cells as mucosal gatekeepers.
- Author
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Cheroutre H
- Abstract
The accumulating failures in HIV vaccine development demonstrate that the immunization approaches used so far are insufficient to reproduce the naturally occurring immunity that controls the virus in long-term non-progressors, HIV controllers, and continuously exposed sex workers. They also underscore the desperate need for new approaches in the design of more effective vaccination protocols. Recent findings might have brought us closer to that goal by providing proof of concept for a novel preventative HIV vaccine by establishing CD8 effector memory T cells within the mucosal sites of transmission.
- Published
- 2009
- Full Text
- View/download PDF
48. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis.
- Author
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Murai M, Turovskaya O, Kim G, Madan R, Karp CL, Cheroutre H, and Kronenberg M
- Subjects
- Adoptive Transfer, Animals, CD11 Antigens immunology, Disease Models, Animal, Forkhead Transcription Factors metabolism, Gene Expression Regulation, Interleukin-10 metabolism, Intestines immunology, Macrophages immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mucous Membrane immunology, Colitis immunology, Forkhead Transcription Factors immunology, Interleukin-10 immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Regulatory T cells (T(reg) cells) that express the transcription factor Foxp3 suppress the activity of other cells. Here we show that interleukin 10 (IL-10) produced by CD11b(+) myeloid cells in recombination-activating gene 1-deficient (Rag1(-/-)) recipient mice was needed to prevent the colitis induced by transferred CD4(+)CD45RB(hi) T cells. In Il10(-/-)Rag1(-/-) mice, T(reg) cells failed to maintain Foxp3 expression and regulatory activity. The loss of Foxp3 expression occurred only in recipients with colitis, which indicates that the requirement for IL-10 is manifested in the presence of inflammation. IL-10 receptor-deficient (Il10rb(-/-)) T(reg) cells also failed to maintain Foxp3 expression, which suggested that host IL-10 acted directly on the T(reg) cells. Our data indicate that IL-10 released from myeloid cells acts in a paracrine manner on T(reg) cells to maintain Foxp3 expression.
- Published
- 2009
- Full Text
- View/download PDF
49. The importance of being earnestly selfish.
- Author
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Cheroutre H, Mucida D, and Lambolez F
- Subjects
- Animals, Humans, Interleukin-17 biosynthesis, Interleukin-17 immunology, T-Lymphocytes cytology, Thymus Gland growth & development, Cell Differentiation immunology, Self Tolerance immunology, T-Lymphocytes immunology, Thymus Gland immunology
- Published
- 2009
- Full Text
- View/download PDF
50. Intestinal T cells: facing the mucosal immune dilemma with synergy and diversity.
- Author
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van Wijk F and Cheroutre H
- Subjects
- Animals, Antigen Presentation, Biomarkers metabolism, CD8 Antigens metabolism, Humans, Immune Tolerance, Immunity, Cellular, Intestinal Mucosa pathology, Lymphocyte Activation, Mice, Mucous Membrane immunology, Mucous Membrane pathology, T-Lymphocyte Subsets pathology, T-Lymphocytes, Regulatory pathology, Immunity, Mucosal, Intestinal Mucosa immunology, Intestines immunology, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism
- Abstract
The epithelium of the gastrointestinal tract, which represents the greatest body surface area exposed to the outside environment, is confronted with a plethora of foreign and potentially harmful antigens. Consequently, the immune system of the gut faces the daunting task of distinguishing harmless dietary proteins and commensal bacteria from potentially dangerous pathogens, and of then responding accordingly. Mucosal T cells play a central role in maintaining barrier function and controlling the delicate balance between immune activation and immune tolerance. This review will focus on the unique features of mucosal T cell subsets that reside in the epithelium and lamina propria of the gut.
- Published
- 2009
- Full Text
- View/download PDF
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