Inhibition of RORγT Skews TCRα Gene Rearrangement and Limits T Cell Repertoire Diversity
| Autor: | Laura Engstrom, Kyle J. Piers, Kenneth Jay Barr, Renu Jain, Dallas C. Jones, Huseyin Mehmet, Heidi Ferguson, Gary D. Glick, John S. Mudgett, Richard Miller, Xiao Hu, Hongjun Zhang, I-Ming Wang, Abbas Hawwari, Craig C. Correll, Barbara Joyce-Shaikh, Razvan Cristescu, Yanxia Guo, Daniel J. Cua, Gretchen A. Baltus, Yi Chen, Thomas Daniel Aicher, Dennis M. Zaller, Laura L. Carter, Laxminarayan G Hegde, Kenzie D. MacIsaac |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
T-cell receptor small-molecule antagonist autoimmunity experimental autoimmune encephalomyelitis Gene rearrangement Biology General Biochemistry Genetics and Molecular Biology Cell biology 03 medical and health sciences Thymocyte 030104 developmental biology lcsh:Biology (General) RAR-related orphan receptor gamma thymopoiesis Immunology Transcriptional regulation RORγT Transcription factor T cell repertoire lcsh:QH301-705.5 CD8 Thymocyte migration experimental psoriasis |
| Zdroj: | Cell Reports, Vol 17, Iss 12, Pp 3206-3218 (2016) |
| ISSN: | 2211-1247 |
| Popis: | Recent studies have elucidated the molecular mechanism of RORγT transcriptional regulation of Th17 differentiation and function. RORγT was initially identified as a transcription factor required for thymopoiesis by maintaining survival of CD4+CD8+ (DP) thymocytes. While RORγ antagonists are currently being developed to treat autoimmunity, it remains unclear how RORγT inhibition may impact thymocyte development. In this study, we show that in addition to regulating DP thymocytes survival, RORγT also controls genes that regulate thymocyte migration, proliferation, and T cell receptor (TCR)α selection. Strikingly, pharmacological inhibition of RORγ skews TCRα gene rearrangement, limits T cell repertoire diversity, and inhibits development of autoimmune encephalomyelitis. Thus, targeting RORγT not only inhibits Th17 cell development and function but also fundamentally alters thymic-emigrant recognition of self and foreign antigens. The analysis of RORγ inhibitors has allowed us to gain a broader perspective of the diverse function of RORγT and its impact on T cell biology. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|