Inhibition of RORγT Skews TCR&alpha ... - Cell Press › publication › fulltext › Inhibition... › publication › fulltext › Inhibition...by Y Guo · 2016 · Cited by 32 · Related articlesDec 20, 2016 — Guo et al. find that small-molecule RORgT
Inhibition of RORgT Skews TCRa Gene Rearrangement and Limits T Cell Repertoire Diversity Graphical Abstract
Authors Yanxia Guo, Kenzie D. MacIsaac, Yi Chen, ..., Craig C. Correll, Dallas C. Jones, Daniel J. Cua
Correspondence
[email protected]
In Brief Guo et al. find that small-molecule RORgT 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 RORgT in clinical testing of RORgT inhibitors.
Highlights d
RORg antagonist treatment recapitulates Rorc-deletioninduced DP thymocyte apoptosis
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RORg regulates genes that control TCRa selection, thymocyte migration, and apoptosis
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RORgT inhibition skews TCRa usage and limits T cell repertoire diversity
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RORg antagonist reduces MOG-tetramer+ TCR precursor frequency and EAE
Guo et al., 2016, Cell Reports 17, 3206–3218 December 20, 2016 ª 2016 The Authors. http://dx.doi.org/10.1016/j.celrep.2016.11.073
Accession Numbers GSE87144 GSE88916
Cell Reports
Article Inhibition of RORgT Skews TCRa Gene Rearrangement and Limits T Cell Repertoire Diversity Yanxia Guo,1,7 Kenzie D. MacIsaac,2,8 Yi Chen,1 Richard J. Miller,2 Renu Jain,1 Barbara Joyce-Shaikh,1 Heidi Ferguson,2 I-Ming Wang,3 Razvan Cristescu,1 John Mudgett,4 Laura Engstrom,2 Kyle J. Piers,2 Gretchen A. Baltus,2 Kenneth Barr,2 Hongjun Zhang,2 Huseyin Mehmet,2 Laxminarayan G. Hegde,2 Xiao Hu,5 Laura L. Carter,5 Thomas D. Aicher,5 Gary Glick,5 Dennis Zaller,2 Abbas Hawwari,6 Craig C. Correll,2 Dallas C. Jones,2,9 and Daniel J. Cua1,10,* 1Merck
Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA 3Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA 4Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA 5Lycera Corp, 2600 Plymouth Road, Ann Arbor, MI 48109, USA 6King 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 7Present address: Immunology Research, Janssen Pharmaceuticals R&D, 1400 McKean Road, Spring House, PA 19477, USA 8Present address: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA 9Present address: Abide Therapeutics, 10835 Road to the Cure, Suite 250, San Diego, CA 92121, USA 10Lead Contact *Correspondence:
[email protected] http://dx.doi.org/10.1016/j.celrep.2016.11.073 2Merck
SUMMARY
Recent studies have elucidated the molecular mechanism of RORgT transcriptional regulation of Th17 differentiation and function. RORgT was initially identified as a transcription factor required for thymopoiesis by maintaining survival of CD4+CD8+ (DP) thymocytes. While RORg antagonists are currently being developed to treat autoimmunity, it remains unclear how RORgT inhibition may impact thymocyte development. In this study, we show that in addition to regulating DP thymocytes survival, RORgT also controls genes that regulate thymocyte migration, proliferation, and T cell receptor (TCR)a selection. Strikingly, pharmacological inhibition of RORg skews TCRa gene rearrangement, limits T cell repertoire diversity, and inhibits development of autoimmune encephalomyelitis. Thus, targeting RORgT not only inhibits Th17 cell development and function but also fundamentally alters thymicemigrant recognition of self and foreign antigens. The analysis of RORg inhibitors has allowed us to gain a broader perspective of the diverse function of RORgT and its impact on T cell biology. INTRODUCTION Retinoic acid receptor-related orphan receptor g T (RORgT) was identified as a lineage-specific transcription factor for Th17 cells (Ivanov et al., 2006; Ciofani et al., 2012) and later shown to be
important for the development of Group 3 innate lymphoid cell residing in the gut and other barrier tissues (Sawa et al., 2011). Rorc gene encodes RORgT with 495 amino acids (aa), which is primarily expressed in thymocytes and Th17 cells. Rorc also encodes a longer isoform designated as RORg with 516 amino acids, which is broadly expressed in muscle, kidney, and liver. The two isoforms differ only in the N-terminal 21 aa with identical ligand binding and DNA binding domains. In the thymus, RORgT is expressed at the highest level in DP thymocytes and is undetectable in other stages of thymocyte development (He et al., 1998). Expression of RORgT is essential for the survival of CD4+CD8+ (DP) thymocytes and its downregulation allows the maturation of CD4 SP and CD8 SP thymocytes (He et al., 2000). Mice deficient in both RORg and RORgT (referred to as Rorc/ hereafter), due to a deletion of the shared DNA-binding domain, showed 60%–80% reduction of DP thymocytes (Sun et al., 2000). Recent identification of small-molecule RORg antagonists have been used to study the regulatory networ
