T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis
| Autor: | Bryce A. Binstadt, João M. Furtado, Michael P. Davey, Paige E. Snow, Biying Xu, Ruth J. Napier, Christina Lancioni, Kimberly A. Samson, Michelle C. Callegan, E. J. Lee, Mary J. Mattapallil, Holly L. Rosenzweig, Emily E. Vance, Sydney Lashley, Reiko Horai, Luke S. Uebelhoer, Brieanna Brown, Rachel R. Caspi, Richard K. Vehe, Justine R. Smith |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
CD4-Positive T-Lymphocytes Male Receptors CCR7 Sarcoidosis T cell Science Nod2 Signaling Adaptor Protein General Physics and Astronomy C-C chemokine receptor type 7 Autoimmunity Biology Signal transduction General Biochemistry Genetics and Molecular Biology Article Uveitis 03 medical and health sciences Mice 0302 clinical medicine Immunity NOD2 NOD-like receptors medicine Animals Humans T-helper 17 cells lcsh:Science Blau syndrome Multidisciplinary Synovitis Arthritis T-cell receptor Interleukin-17 MUTAÇÃO GENÉTICA General Chemistry medicine.disease digestive system diseases Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Immunology Th17 Cells Female lcsh:Q Ligation 030215 immunology |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020) Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod2 are well-established, yet the cellular mechanisms by which dysregulated Nod2 causes uveitis remain unknown. Here, we report a non-conventional, T cell-intrinsic function for Nod2 in suppression of Th17 immunity and experimental uveitis. Reconstitution of lymphopenic hosts with Nod2−/− CD4+ T cells or retina-specific autoreactive CD4+ T cells lacking Nod2 reveals a T cell-autonomous, Rip2-independent mechanism for Nod2 in uveitis. In naive animals, Nod2 operates downstream of TCR ligation to suppress activation of memory CD4+ T cells that associate with an autoreactive-like profile involving IL-17 and Ccr7. Interestingly, CD4+ T cells from two Blau syndrome patients show elevated IL-17 and increased CCR7. Our data define Nod2 as a T cell-intrinsic rheostat of Th17 immunity, and open new avenues for T cell-based therapies for Nod2-associated disorders such as Blau syndrome. How mutations in the microbial receptor NOD2 induce Blau syndrome in humans and related uveitis is unclear. Here the authors show, using Nod2-deficient mice and experimental uveitis, that Nod2 negatively regulates T cell activation and transcription of autoimmunity-related genes to suppress Th17 responses and uveitis. |
| Databáze: | OpenAIRE |
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