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

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 currentl...

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Vydáno v:	Cell reports (Cambridge) Ročník 17; číslo 12; s. 3206 - 3218
Hlavní autoři:	Guo, Yanxia, MacIsaac, Kenzie D., Chen, Yi, Miller, Richard J., Jain, Renu, Joyce-Shaikh, Barbara, Ferguson, Heidi, Wang, I-Ming, Cristescu, Razvan, Mudgett, John, Engstrom, Laura, Piers, Kyle J., Baltus, Gretchen A., Barr, Kenneth, Zhang, Hongjun, Mehmet, Huseyin, Hegde, Laxminarayan G., Hu, Xiao, Carter, Laura L., Aicher, Thomas D., Glick, Gary, Zaller, Dennis, Hawwari, Abbas, Correll, Craig C., Jones, Dallas C., Cua, Daniel J.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Elsevier Inc 20.12.2016 Elsevier
Témata:	Animals Antigens - immunology autoimmunity CD4-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - immunology Cell Differentiation - genetics Encephalomyelitis, Autoimmune, Experimental - genetics Encephalomyelitis, Autoimmune, Experimental - immunology Encephalomyelitis, Autoimmune, Experimental - therapy experimental autoimmune encephalomyelitis experimental psoriasis Gene Expression Regulation - immunology Gene Rearrangement - genetics Humans Mice Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics Nuclear Receptor Subfamily 1, Group F, Member 3 - immunology Receptors, Antigen, T-Cell, alpha-beta - antagonists & inhibitors Receptors, Antigen, T-Cell, alpha-beta - genetics Receptors, Antigen, T-Cell, alpha-beta - immunology RORγT small-molecule antagonist T cell repertoire Th17 Cells - drug effects Th17 Cells - immunology Thymocytes - immunology thymopoiesis experimental autoimmune encephalomyelitis autoimmunity thymopoiesis T cell repertoire experimental psoriasis RORγT small-molecule antagonist
ISSN:	2211-1247, 2211-1247
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Shrnutí:	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. [Display omitted] •RORγ antagonist treatment recapitulates Rorc-deletion-induced DP thymocyte apoptosis•RORγ regulates genes that control TCRα selection, thymocyte migration, and apoptosis•RORγT inhibition skews TCRα usage and limits T cell repertoire diversity•RORγ antagonist reduces MOG-tetramer+ TCR precursor frequency and EAE Guo et al. find that small-molecule RORγT antagonist treatment induces CD4+CD8+ thymocyte apoptosis, skews the T cell repertoire, prevents autoreactive T cell development, and delays autoimmune EAE progression. This work underscores the risk versus benefit of targeting RORγT in clinical testing of RORγT inhibitors.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2016.11.073