title: Inhibition of RORγT Skews TCRα Gene Rearrangement and Limits T Cell Repertoire Diversity.
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.
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Kenzie D
authors.initials: KD
authors.lastname: MacIsaac
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Miller
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Renu
authors.initials: R
authors.lastname: Jain
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Joyce-Shaikh
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Ferguson
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Wang
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors.forename: Razvan
authors.initials: R
authors.lastname: Cristescu
authors.affiliation: Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: John
authors.initials: J
authors.lastname: Mudgett
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Engstrom
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Piers
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Gretchen A
authors.initials: GA
authors.lastname: Baltus
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Barr
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Huseyin
authors.initials: H
authors.lastname: Mehmet
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Laxminarayan G
authors.initials: LG
authors.lastname: Hegde
authors.affiliation: Lycera Corp, 2600 Plymouth Road, Ann Arbor, MI 48109, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.affiliation: Lycera Corp, 2600 Plymouth Road, Ann Arbor, MI 48109, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Carter
authors.affiliation: Lycera Corp, 2600 Plymouth Road, Ann Arbor, MI 48109, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Aicher
authors.affiliation: Lycera Corp, 2600 Plymouth Road, Ann Arbor, MI 48109, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Glick
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Zaller
authors.affiliation: 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.
authors.forename: Abbas
authors.initials: A
authors.lastname: Hawwari
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Craig C
authors.initials: CC
authors.lastname: Correll
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Dallas C
authors.initials: DC
authors.lastname: Jones
authors.affiliation: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA. Electronic address: daniel.cua@merck.com.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cua
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D005786:Gene Expression Regulation / Q000276:immunology; D015321:Gene Rearrangement / Q000235:genetics; D006801:Humans; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics* / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D060168:Thymocytes / Q000276:immunology*
chemical_list: D000941:Antigens; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D016693:Receptors, Antigen, T-Cell, alpha-beta
keywords: RORγT; T cell repertoire; autoimmunity; experimental autoimmune encephalomyelitis; experimental psoriasis; small-molecule antagonist; thymopoiesis