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

Inhibition of RORγT Skews TCRα Gene Rearrangement and Limits T Cell Repertoire Diversity.
Author Information (click to view)

Guo Y, MacIsaac KD, Chen Y, Miller RJ, Jain R, Joyce-Shaikh B, Ferguson H, Wang IM, Cristescu R, Mudgett J, Engstrom L, Piers KJ, Baltus GA, Barr K, Zhang H, Mehmet H, Hegde LG, Hu X, Carter LL, Aicher TD, Glick G, Zaller D, Hawwari A, Correll CC, Jones DC, Cua DJ,


Guo Y, MacIsaac KD, Chen Y, Miller RJ, Jain R, Joyce-Shaikh B, Ferguson H, Wang IM, Cristescu R, Mudgett J, Engstrom L, Piers KJ, Baltus GA, Barr K, Zhang H, Mehmet H, Hegde LG, Hu X, Carter LL, Aicher TD, Glick G, Zaller D, Hawwari A, Correll CC, Jones DC, Cua DJ, (click to view)

Guo Y, MacIsaac KD, Chen Y, Miller RJ, Jain R, Joyce-Shaikh B, Ferguson H, Wang IM, Cristescu R, Mudgett J, Engstrom L, Piers KJ, Baltus GA, Barr K, Zhang H, Mehmet H, Hegde LG, Hu X, Carter LL, Aicher TD, Glick G, Zaller D, Hawwari A, Correll CC, Jones DC, Cua DJ,

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Cell reports 17(12) 3206-3218 pii 10.1016/j.celrep.2016.11.073

Abstract

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.

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