دورية أكاديمية
DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs.
العنوان: | DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs. |
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المؤلفون: | Janssen E; Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA., Kumari S; Department of Bioengineering and Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Tohme M; Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA., Ullas S; Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA., Barrera V; Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA., Tas JM; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA., Castillo-Rama M; Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA., Bronson RT; Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Usmani SM; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA., Irvine DJ; Department of Bioengineering and Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Mempel TR; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA., Geha RS; Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA. |
المصدر: | JCI insight [JCI Insight] 2017 Oct 05; Vol. 2 (19). Date of Electronic Publication: 2017 Oct 05. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
اللغة: | English |
بيانات الدورية: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight |
أسماء مطبوعة: | Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]- |
مواضيع طبية MeSH: | Guanine Nucleotide Exchange Factors/*immunology , Immune Tolerance/*immunology , Immunological Synapses/*immunology , Interleukin-2/*immunology , T-Lymphocytes, Regulatory/*immunology, Animals ; Autoantibodies/biosynthesis ; Autoimmunity/immunology ; CD4-Positive T-Lymphocytes/immunology ; Gastroenteritis/immunology ; Guanine Nucleotide Exchange Factors/deficiency ; Inflammation/immunology ; Lymph Nodes/immunology ; Mice, Knockout ; Phosphorylation/immunology ; STAT5 Transcription Factor/metabolism ; Weight Gain/immunology |
مستخلص: | Patients deficient in the guanine nucleotide exchange factor DOCK8 have decreased numbers and impaired in vitro function of Tregs and make autoantibodies, but they seldom develop autoimmunity. We show that, similarly, Dock8-/- mice have decreased numbers and impaired in vitro function of Tregs but do not develop autoimmunity. In contrast, mice with selective DOCK8 deficiency in Tregs develop lymphoproliferation, autoantibodies, and gastrointestinal inflammation, despite a normal percentage and in vitro function of Tregs, suggesting that deficient T effector cell function might protect DOCK8-deficient patients from autoimmunity. We demonstrate that DOCK8 associates with STAT5 and is important for IL-2-driven STAT5 phosphorylation in Tregs. DOCK8 localizes within the lamellar actin ring of the Treg immune synapse (IS). Dock8-/- Tregs have abnormal TCR-driven actin dynamics, decreased adhesiveness, an altered gene expression profile, an unstable IS with decreased recruitment of signaling molecules, and impaired transendocytosis of the costimulatory molecule CD86. These data suggest that DOCK8 enforces immunological tolerance by promoting IL-2 signaling, TCR-driven actin dynamics, and the IS in Tregs. |
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معلومات مُعتمدة: | K08 AI114968 United States AI NIAID NIH HHS; P01 AI078897 United States AI NIAID NIH HHS; P30 DK043351 United States DK NIDDK NIH HHS |
المشرفين على المادة: | 0 (Autoantibodies) 0 (Dock8 protein, mouse) 0 (Guanine Nucleotide Exchange Factors) 0 (Interleukin-2) 0 (STAT5 Transcription Factor) |
تواريخ الأحداث: | Date Created: 20171006 Date Completed: 20190729 Latest Revision: 20200306 |
رمز التحديث: | 20240628 |
مُعرف محوري في PubMed: | PMC5841868 |
DOI: | 10.1172/jci.insight.94298 |
PMID: | 28978806 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2379-3708 |
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DOI: | 10.1172/jci.insight.94298 |