Cell Reports (Dec 2016)
Inhibition of RORγT Skews TCRα Gene Rearrangement and Limits T Cell Repertoire Diversity
- 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
Affiliations
- Yanxia Guo
- Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA
- Kenzie D. MacIsaac
- Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
- Yi Chen
- Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA
- Richard J. Miller
- Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
- Renu Jain
- Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA
- Barbara Joyce-Shaikh
- Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA
- Heidi Ferguson
- Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
- I-Ming Wang
- Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA
- Razvan Cristescu
- Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA
- John Mudgett
- Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA
- Laura Engstrom
- Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
- Kyle J. Piers
- Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
- Gretchen A. Baltus
- Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
- Kenneth Barr
- Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
- Hongjun Zhang
- Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
- Huseyin Mehmet
- Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
- Laxminarayan G. Hegde
- Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
- Xiao Hu
- Lycera Corp, 2600 Plymouth Road, Ann Arbor, MI 48109, USA
- Laura L. Carter
- Lycera Corp, 2600 Plymouth Road, Ann Arbor, MI 48109, USA
- Thomas D. Aicher
- Lycera Corp, 2600 Plymouth Road, Ann Arbor, MI 48109, USA
- Gary Glick
- Lycera Corp, 2600 Plymouth Road, Ann Arbor, MI 48109, USA
- Dennis Zaller
- Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
- Abbas Hawwari
- King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City Hospital, Ministry of National Guard Health Affairs, Mail Code 520, P.O. Box 6664, Al Hasa 31982, Kingdom of Saudi Arabia
- Craig C. Correll
- Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
- Dallas C. Jones
- Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
- Daniel J. Cua
- Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA
- DOI
- https://doi.org/10.1016/j.celrep.2016.11.073
- Journal volume & issue
-
Vol. 17,
no. 12
pp. 3206 – 3218
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.
Keywords
- RORγT
- small-molecule antagonist
- thymopoiesis
- T cell repertoire
- autoimmunity
- experimental autoimmune encephalomyelitis
- experimental psoriasis
