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

被引：50

作者：

Guo, Yanxia ^{[1
,7
]}

MacIsaac, Kenzie D. ^{[2
,8
]}

Chen, Yi ^{[1
]}

Miller, Richard J. ^{[2
]}

Jain, Renu ^{[1
]}

Joyce-Shaikh, Barbara ^{[1
]}

Ferguson, Heidi ^{[2
]}

Wang, I-Ming ^{[3
]}

Cristescu, Razvan ^{[1
]}

Mudgett, John ^{[4
]}

Engstrom, Laura ^{[2
]}

Piers, Kyle J. ^{[2
]}

Baltus, Gretchen A. ^{[2
]}

Barr, Kenneth ^{[2
]}

Zhang, Hongjun ^{[2
]}

Mehmet, Huseyin ^{[2
]}

Hegde, Laxminarayan G. ^{[2
]}

Hu, Xiao ^{[5
]}

Carter, Laura L. ^{[5
]}

Aicher, Thomas D. ^{[5
]}

Glick, Gary ^{[5
]}

Zaller, Dennis ^{[2
]}

Hawwari, Abbas ^{[6
]}

Correll, Craig C. ^{[2
]}

Jones, Dallas C. ^{[2
,9
]}

Cua, Daniel J. ^{[1
]}

机构：

[1] Merck Res Labs, 901 Calif Ave, Palo Alto, CA 94304 USA

[2] Merck Res Labs, 33 Ave Louis Pasteur, Boston, MA 02115 USA

[3] Merck Res Labs, 770 Sumneytown Pike, West Point, PA 19486 USA

[4] Merck Res Labs, 2000 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[5] Lycera Corp, 2600 Plymouth Rd, Ann Arbor, MI 48109 USA

[6] King Saud Bin Abdulaziz Univ Hlth Sci, King Abdulaziz Med City Hosp, Minist Natl Guard Hlth Affairs, KAIMRC, Mail Code 520,POB 6664, Al Hasa 31982, Saudi Arabia

[7] Janssen Pharmaceut R&D, Immunol Res, 1400 McKean Rd, Spring House, PA 19477 USA

[8] Novartis Inst Biomed Res, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[9] Abide Therapeut, 10835 Rd Cure,Suite 250, San Diego, CA 92121 USA

来源：

CELL REPORTS | 2016年 / 17卷 / 12期

关键词：

CD4(+)CD8(+) THYMOCYTES; ORPHAN RECEPTOR; DIFFERENTIATION; SURVIVAL; EXPRESSION; MIGRATION; IMMUNITY; NETWORK; PROTEIN; IL-17C;

D O I：

10.1016/j.celrep.2016.11.073

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Recent studies have elucidated the molecular mechanism of ROR gamma T transcriptional regulation of Th17 differentiation and function. ROR gamma T was initially identified as a transcription factor required for thymopoiesis by maintaining survival of CD4(+)CD8(+) (DP) thymocytes. While ROR gamma antagonists are currently being developed to treat autoimmunity, it remains unclear how ROR gamma T inhibition may impact thymocyte development. In this study, we show that in addition to regulating DP thymocytes survival, ROR gamma T also controls genes that regulate thymocyte migration, proliferation, and T cell receptor (TCR)alpha selection. Strikingly, pharmacological inhibition of ROR gamma skews TCR alpha gene rearrangement, limits T cell repertoire diversity, and inhibits development of autoimmune encephalomyelitis. Thus, targeting ROR gamma T not only inhibits Th17 cell development and function but also fundamentally alters thymicemigrant recognition of self and foreign antigens. The analysis of ROR gamma inhibitors has allowed us to gain a broader perspective of the diverse function of ROR gamma T and its impact on T cell biology.

引用

页码：3206 / 3218

页数：13

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