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Immunity. 2018 Apr 17;48(4):745-759.e6. doi: 10.1016/j.immuni.2018.03.025.

T Cell Receptor-Regulated TGF-β Type I Receptor Expression Determines T Cell Quiescence and Activation.

Author information

1
Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA.
2
Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
3
Department of Medicine, University of Chicago, Chicago, IL, USA.
4
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
5
Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China. Electronic address: lingyunsun@nju.edu.cn.
6
Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA. Electronic address: wchen@mail.nih.gov.

Abstract

It is unclear how quiescence is enforced in naive T cells, but activation by foreign antigens and self-antigens is allowed, despite the presence of inhibitory signals. We showed that active transforming growth factor β (TGF-β) signaling was present in naive T cells, and T cell receptor (TCR) engagement reduced TGF-β signaling during T cell activation by downregulating TGF-β type 1 receptor (TβRI) through activation of caspase recruitment domain-containing protein 11 (CARD11) and nuclear factor κB (NF-κB). TGF-β prevented TCR-mediated TβRI downregulation, but this was abrogated by interleukin-6 (IL-6). Mitigation of TCR-mediated TβRI downregulation through overexpression of TβRI in naive and activated T cells rendered T cells less responsive and suppressed autoimmunity. Naive T cells in autoimmune patients exhibited reduced TβRI expression and increased TCR-driven proliferation compared to healthy subjects. Thus, TCR-mediated regulation of TβRI-TGF-β signaling acts as a crucial criterion to determine T cell quiescence and activation.

KEYWORDS:

CARD11; IL-6; NF-kB; T cell activation; T cell quiescence; TCR signaling; TGF-β; autoimmunity; receptor I downregulation; signaling

PMID:
29669252
PMCID:
PMC5911925
DOI:
10.1016/j.immuni.2018.03.025
[Indexed for MEDLINE]
Free PMC Article

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