Inhibition of RORγT Skews TCRα Gene Rearrangement and Limits T Cell Repertoire Diversity

• Main Authors: Yanxia Guo, Kenzie D. MacIsaac, Yi Chen, Richard J. Miller, Renu Jain, Barbara Joyce-Shaikh, Heidi Ferguson, I-Ming Wang, Razvan Cristescu, John Mudgett, Laura Engstrom, Kyle J. Piers, Gretchen A. Baltus, Kenneth Barr, Hongjun Zhang, Huseyin Mehmet, Laxminarayan G. Hegde, Xiao Hu, Laura L. Carter, Thomas D. Aicher, Gary Glick, Dennis Zaller, Abbas Hawwari, Craig C. Correll, Dallas C. Jones, Daniel J. Cua
• Format: Article
• Language: English
• Published: Elsevier 2016-12-01
• Series: Cell Reports
• Subjects: RORγT; small-molecule antagonist; thymopoiesis; T cell repertoire; autoimmunity; experimental autoimmune encephalomyelitis; experimental psoriasis
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124716316473

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.