8 results on '"S. Gilfillan"'
Search Results
2. DC-SCRIPT deficiency delays mouse mammary gland development and branching morphogenesis.
- Author
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Tang C, van den Bijgaart RJE, Looman MWG, Tel-Karthaus N, de Graaf AMA, Gilfillan S, Colonna M, Ansems M, and Adema GJ
- Subjects
- Animals, Cell Culture Techniques methods, Cell Cycle Checkpoints genetics, DNA-Binding Proteins deficiency, Epithelial Cells metabolism, Epithelium growth & development, Epithelium metabolism, Female, Gene Expression Regulation, Developmental, Homeostasis genetics, Mammary Glands, Animal growth & development, Mice, Inbred C57BL, Mice, Knockout, Nuclear Proteins deficiency, Organoids cytology, Organoids growth & development, Transcription Factors deficiency, DNA-Binding Proteins genetics, Mammary Glands, Animal metabolism, Morphogenesis genetics, Nuclear Proteins genetics, Organoids metabolism, Transcription Factors genetics
- Abstract
Mammary glands are unique organs in which major adaptive changes occur in morphogenesis and development after birth. Breast cancer is the most common cancer and a major cause of mortality in females worldwide. We have previously identified the loss of expression of the transcription regulator DC-SCRIPT (Zfp366) as a prominent prognostic event in estrogen receptor positive breast cancer patients. DC-SCRIPT affects multiple transcriptional events in breast cancer cells, including estrogen and progesterone receptor-mediated transcription, and promotes CDKN2B-related cell cycle arrest. As loss of DC-SCRIPT expression appears an early event in breast cancer development, we here investigated the role of DC-SCRIPT in mammary gland development using wild-type and DC-SCRIPT knockout mice. Mice lacking DC-SCRIPT exhibited severe breeding problems and showed significant growth delay relative to littermate wild-type mice. Subsequent analysis revealed that DC-SCRIPT was expressed in mouse mammary epithelium and that DC-SCRIPT deficiency delayed mammary gland morphogenesis in vivo. Finally, analysis of 3D mammary gland organoid cultures confirmed that loss of DC-SCRIPT dramatically delayed mammary organoid branching in vitro. The study shows for the first time that DC-SCRIPT deficiency delays mammary gland morphogenesis in vivo and in vitro. These data define DC-SCRIPT as a novel modulator of mammary gland development., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
3. Jak3 deficiency blocks innate lymphoid cell development.
- Author
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Robinette ML, Cella M, Telliez JB, Ulland TK, Barrow AD, Capuder K, Gilfillan S, Lin LL, Notarangelo LD, and Colonna M
- Subjects
- Animals, Cell Differentiation genetics, Cell Proliferation genetics, Cells, Cultured, Humans, Immunity, Innate, Interferon-gamma metabolism, Janus Kinase 3 antagonists & inhibitors, Mice, Mice, Mutant Strains, Phenotype, Piperidines pharmacology, Pyrimidines pharmacology, Pyrroles pharmacology, Arthritis, Rheumatoid drug therapy, Bone Marrow Cells physiology, Janus Kinase 3 genetics, Killer Cells, Natural physiology, Mutation genetics, Piperidines therapeutic use, Pyrimidines therapeutic use, Pyrroles therapeutic use, Severe Combined Immunodeficiency genetics
- Abstract
Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive severe combined immunodeficiency (SCID). Defects in this form of SCID are restricted to the immune system, which led to the development of immunosuppressive JAK inhibitors. We find that the B6.Cg-Nr1d1
tm1Ven /LazJ mouse line purchased from Jackson Laboratories harbors a spontaneous mutation in Jak3, generating a SCID phenotype and an inability to generate antigen-independent professional cytokine-producing innate lymphoid cells (ILCs). Mechanistically, Jak3 deficiency blocks ILC differentiation in the bone marrow at the ILC precursor and the pre-NK cell progenitor. We further demonstrate that the pan-JAK inhibitor tofacitinib and the specific JAK3 inhibitor PF-06651600 impair the ability of human intraepithelial ILC1 (iILC1) to produce IFN-γ, without affecting ILC3 production of IL-22. Both inhibitors impaired the proliferation of iILC1 and ILC3 and differentiation of human ILC in vitro. Tofacitinib is currently approved for the treatment of moderate-to-severely active rheumatoid arthritis. Both tofacitinib and PF-06651600 are currently in clinical trials for several other immune-mediated conditions. Our data suggest that therapeutic inhibition of JAK may also impact ILCs and, to some extent, underlie clinical efficacy.- Published
- 2018
- Full Text
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4. Microbiota induces tonic CCL2 systemic levels that control pDC trafficking in steady state.
- Author
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Swiecki M, Miller HL, Sesti-Costa R, Cella M, Gilfillan S, and Colonna M
- Subjects
- Animals, Apoptosis, Cells, Cultured, Cytokines metabolism, Homeostasis, Inflammation microbiology, Inflammation Mediators metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mononuclear Phagocyte System, Receptors, CCR2 genetics, Receptors, CCR2 metabolism, Specific Pathogen-Free Organisms, Cell Movement, Chemokine CCL2 metabolism, Dendritic Cells immunology, Inflammation immunology, Microbiota immunology
- Abstract
Plasmacytoid dendritic cells (pDCs) detect viruses initiating antiviral type I interferon responses. The microbiota is known to shape immune responses, but whether it influences pDC homeostasis and/or function is poorly understood. By comparing pDCs in germ-free and specific pathogen-free mice, we found that the microbiota supports homeostatic trafficking by eliciting constitutive levels of the chemokine CCL2 that engages CCR2. Mononuclear phagocytes were required for tonic CCL2 levels. CCL2 was particularly important for trafficking of a CCR2
hi subset of pDCs that produced proinflammatory cytokines and was prone to apoptosis. We further demonstrated that CCR2 was also essential for pDC migration during inflammation. Wild-type (WT):Ccr2-/- mixed bone marrow chimeras revealed that CCR2 promotes pDC migration in a cell-intrinsic manner. Overall, we identify a novel role for the microbiota in shaping immunity, which includes induction of CCL2 levels that control homeostatic trafficking of pDCs.- Published
- 2017
- Full Text
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5. DAP10 contributes to CD8(+) T cell-mediated cytotoxic effector mechanisms during Mycobacterium tuberculosis infection.
- Author
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Hessmann M, Rausch A, Rückerl D, Adams PS, Simon M, Gilfillan S, Colonna M, Ehlers S, and Hölscher C
- Subjects
- Animals, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes microbiology, CD8-Positive T-Lymphocytes pathology, Cell Count, Cells, Cultured, Disease Models, Animal, Humans, Interferon-gamma metabolism, Lymphocyte Activation genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Mycobacterium tuberculosis pathogenicity, Receptors, Immunologic genetics, Receptors, Immunologic immunology, Tuberculosis, Pulmonary drug therapy, CD8-Positive T-Lymphocytes metabolism, Cytotoxicity, Immunologic genetics, Mycobacterium tuberculosis immunology, Receptors, Immunologic metabolism, Tuberculosis, Pulmonary immunology
- Abstract
The activating C-type lectin-like receptor NKG2D, which is expressed by mouse NK cells and activated CD8 T cells, was previously demonstrated to be involved in tumor rejection and as a defense mechanism against viral and bacterial infections. Because CD8 T cells are important for protective immune responses during chronic Mycobacterium tuberculosis (Mtb) infection and represent a promising target for new vaccine strategies to prevent human pulmonary tuberculosis (TB), we studied the immune response in mice deficient for the NKG2D adapter molecule DAP10 during experimental TB. After aerosol infection, DAP10-defcient mice displayed an unimpaired recruitment, activation and development of antigen-specific CD8 T cells. Whereas the frequency of interferon-gamma-producing CD8 T cells from Mtb-infected DAP10-defcient mice was not affected, CD8 T cell-mediated cytotoxicity was significantly reduced in the absence of DAP10. The loss of cytotoxic activity in DAP10-deficient CD8 T cells was associated with an impaired release of cytotoxic granules. Together, our results suggest that during Mtb infection DAP10 is required for maximal cytolytic activity of CD8 T cells., (Copyright © 2010 Elsevier GmbH. All rights reserved.)
- Published
- 2011
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6. ITAM signaling in dendritic cells controls T helper cell priming by regulating MHC class II recycling.
- Author
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Graham DB, Akilesh HM, Gmyrek GB, Piccio L, Gilfillan S, Sim J, Belizaire R, Carrero JA, Wang Y, Blaufuss GS, Sandoval G, Fujikawa K, Cross AH, Russell JH, Cella M, and Swat W
- Subjects
- Amino Acid Motifs, Animals, Antigen Presentation, Brain Diseases chemically induced, Brain Diseases immunology, CD4-Positive T-Lymphocytes immunology, Encephalitis, Hashimoto Disease chemically induced, Hashimoto Disease immunology, Histocompatibility Antigens Class II metabolism, Lysosomes metabolism, Mice, Signal Transduction, Tyrosine immunology, Ubiquitination, Adaptor Proteins, Signal Transducing immunology, Dendritic Cells immunology, Histocompatibility Antigens Class II immunology, Proto-Oncogene Proteins c-vav immunology, Receptors, IgG immunology, T-Lymphocytes, Helper-Inducer immunology
- Abstract
Immature dendritic cells (DCs) specialize in antigen capture and maintain a highly dynamic pool of intracellular major histocompatibility complex class II (MHCII) that continuously recycles from peptide loading compartments to the plasma membrane and back again. This process facilitates sampling of environmental antigens for presentation to T helper cells. Here, we show that a signaling pathway mediated by the DC immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors (DAP12 and FcRγ) and Vav family guanine nucleotide exchange factors controls the half-life of surface peptide-MHCII (pMHCII) complexes and is critical for CD4 T-cell triggering in vitro. Strikingly, mice with disrupted DC ITAMs show defective T helper cell priming in vivo and are protected from experimental autoimmune encephalitis. Mechanistically, we show that deficiency in ITAM signaling results in increased pMHCII internalization, impaired recycling, and an accumulation of ubiquitinated MHCII species that are prematurely degraded in lysosomes. We propose a novel mechanism for control of T helper cell priming.
- Published
- 2010
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7. NK cell-activating receptors require PKC-theta for sustained signaling, transcriptional activation, and IFN-gamma secretion.
- Author
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Tassi I, Cella M, Presti R, Colucci A, Gilfillan S, Littman DR, and Colonna M
- Subjects
- Animals, Interferon-gamma immunology, Isoenzymes genetics, Isoenzymes immunology, JNK Mitogen-Activated Protein Kinases immunology, JNK Mitogen-Activated Protein Kinases metabolism, Killer Cells, Natural immunology, Mice, Mice, Knockout, NF-kappa B immunology, NF-kappa B metabolism, NFATC Transcription Factors immunology, NFATC Transcription Factors metabolism, Protein Kinase C genetics, Protein Kinase C immunology, Protein Kinase C-theta, Transcription Factor AP-1 immunology, Transcription Factor AP-1 metabolism, Interferon-gamma metabolism, Isoenzymes metabolism, Killer Cells, Natural enzymology, Protein Kinase C metabolism, Signal Transduction physiology
- Abstract
Natural killer (NK) cell sense virally infected cells and tumor cells through multiple cell surface receptors. Many NK cell-activating receptors signal through immunoreceptor tyrosine-based activation motif (ITAM)-containing adapters, which trigger both cytotoxicy and secretion of interferon-gamma (IFN-gamma). Within the ITAM pathway, distinct signaling intermediates are variably involved in cytotoxicity and/or IFN-gamma secretion. In this study, we have evaluated the role of protein kinase C- (PKC-) in NK-cell secretion of lytic mediators and IFN-gamma. We found that engagement of NK-cell receptors that signal through ITAMs results in prompt activation of PKC-. Analyses of NK cells from PKC--deficient mice indicated that PKC- is absolutely required for ITAM-mediated IFN-gamma secretion, whereas it has no marked influence on the release of cytolytic mediators. Moreover, we found that PKC- deficiency preferentially impairs sustained extracellular-regulated kinase signaling as well as activation of c-Jun N-terminal kinase and the transcription factors AP-1 and NFAT but does not affect activation of NF-kappaB. These results indicate that NK cell-activating receptors require PKC- to generate sustained intracellular signals that reach the nucleus and promote transcriptional activation, ultimately inducing IFN-gamma production.
- Published
- 2008
- Full Text
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8. Mucosal-associated invariant T (MAIT) cells: an evolutionarily conserved T cell subset.
- Author
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Treiner E, Duban L, Moura IC, Hansen T, Gilfillan S, and Lantz O
- Subjects
- Animals, Gene Expression, Humans, Intestinal Mucosa immunology, Killer Cells, Natural immunology, Biological Evolution, Immunity, Mucosal, T-Lymphocyte Subsets immunology
- Abstract
Besides mainstream TCRalphabeta T cells harboring a very diverse repertoire, two subsets display an evolutionarily conserved invariant repertoire. This striking conservation indicates important and unique functions. CD1d-restricted NK-T cells expressing an invariant Valpha14 TCRalpha chain have been implicated in microbial and tumor responses as well as in auto-immunity. In this review, we describe the other subset, which bears the canonical hValpha7.2/mValpha19-Jalpha33 TCRalpha chain paired with a restricted set of Vbeta segments. These invariant T cells are present in mice, humans and cattle. They are preferentially located in the gut lamina propria (LP) of humans and mice and are therefore called mucosal-associated invariant T (MAIT) cells. Selection/expansion of this population requires B lymphocytes expressing MR1, a monomorphic major histocompatibility complex class I-related molecule that is also strikingly conserved in diverse mammalian species. MAIT cells are not present in germ-free mice, indicating that commensal flora is required for their expansion in the gut LP. The nature of the ligand and the putative functions of these MAIT cells are discussed.
- Published
- 2005
- Full Text
- View/download PDF
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