RORα is critical for mTORC1 activity in T cell-mediated colitis

Xinxin Chi; Wei Jin; Xue Bai; Xiaohong Zhao; Jing Shao; Jiaqi Li; Qinli Sun; Bing Su; Xiaohu Wang; Xuexian O Yang; Chen Dong

doi:10.1016/j.celrep.2021.109682

RORα is critical for mTORC1 activity in T cell-mediated colitis

Cell Rep. 2021 Sep 14;36(11):109682. doi: 10.1016/j.celrep.2021.109682.

Authors

Xinxin Chi¹, Wei Jin², Xue Bai², Xiaohong Zhao², Jing Shao², Jiaqi Li², Qinli Sun², Bing Su³, Xiaohu Wang², Xuexian O Yang⁴, Chen Dong⁵

Affiliations

¹ Institute for Immunology, Tsinghua University, Beijing 100084, China; School of Life Science, Tsinghua University, Beijing 100084, China.
² Institute for Immunology, Tsinghua University, Beijing 100084, China.
³ Shanghai Institute of Immunology, Department of Immunology and Microbiology, and The State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁴ Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
⁵ Institute for Immunology, Tsinghua University, Beijing 100084, China; Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai 200127, China. Electronic address: [email protected].

PMID: 34525365
DOI: 10.1016/j.celrep.2021.109682

Abstract

Inflammatory bowel disease (IBD) is multi-factorial chronic intestinal inflammation driven by pathogenic T cells, among which a large portion of patients are resistant to current anti-inflammatory regimes. The mechanisms underlying colitis pathogenicity and drug resistance are not fully understood. Here, we demonstrate that RORα is highly expressed in active UC patients, particularly in those non-responsive to anti-TNF treatment. Rorα deficiency in CD4⁺ T cells greatly reduced colitis development. Mechanistically, RORα regulated T cell infiltration in colon and inhibited T cell apoptosis. Meanwhile, genome-wide occupancy and transcriptome analysis revealed that RORα promoted mTORC1 activation. mTORC1 signaling, also hyperactivated in active UC patients, is necessary for T cell-mediated colitis. Our results thus demonstrate a crucial role of the RORα-mTORC1 axis in CD4⁺ T cells in promoting IBD, which may be targeted in human patients.

Keywords: CD4(+) T cells; RORα; anti-TNF therapy; colitis; mTORC1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
CD4-Positive T-Lymphocytes / cytology
CD4-Positive T-Lymphocytes / immunology*
CD4-Positive T-Lymphocytes / metabolism
Colitis, Ulcerative / drug therapy
Colitis, Ulcerative / immunology
Colitis, Ulcerative / metabolism
Colitis, Ulcerative / pathology*
Colon / immunology
Colon / pathology
Disease Models, Animal
Drug Resistance, Neoplasm / genetics
Female
Humans
Infliximab / therapeutic use
Interleukin-17 / genetics
Interleukin-17 / metabolism
Mechanistic Target of Rapamycin Complex 1 / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Nuclear Receptor Subfamily 1, Group F, Member 1 / deficiency
Nuclear Receptor Subfamily 1, Group F, Member 1 / genetics
Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism*
Signal Transduction
T-Box Domain Proteins / genetics
T-Box Domain Proteins / metabolism
T-bet Transcription Factor
Th17 Cells / cytology
Th17 Cells / immunology
Th17 Cells / metabolism

Substances

IL17A protein, human
Interleukin-17
Nuclear Receptor Subfamily 1, Group F, Member 1
Rora protein, mouse
T-Box Domain Proteins
T-bet Transcription Factor
Infliximab
Mechanistic Target of Rapamycin Complex 1