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

• Published in: Immunity (Cambridge, Mass.) Vol. 48; no. 4; pp. 745 - 759.e6
• Main Authors: Tu, Eric, Chia, Cheryl P.Z., Chen, Weiwei, Zhang, Dunfang, Park, Sang A., Jin, Wenwen, Wang, Dandan, Alegre, Maria-Luisa, Zhang, Ying E., Sun, Lingyun, Chen, WanJun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.04.2018; Elsevier Limited
• Subjects: Animals; Antigens; Autoantigens; Autoimmunity; Autoimmunity - immunology; CARD Signaling Adaptor Proteins - genetics; CARD Signaling Adaptor Proteins - metabolism; CARD11; Caspase; CD4-Positive T-Lymphocytes - immunology; Cell activation; Cell Line; Cell Proliferation; Colitis - immunology; Colitis - pathology; Disease Models, Animal; Down-Regulation - immunology; Experiments; Guanylate Cyclase - genetics; Guanylate Cyclase - metabolism; HEK293 Cells; Humans; IL-6; Interleukin 6; Interleukin-6 - immunology; Lupus Erythematosus, Systemic - immunology; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - metabolism; NF-kB; NF-κB protein; Proteins; R&D; receptor I downregulation; Receptor, Transforming Growth Factor-beta Type I - biosynthesis; Receptor, Transforming Growth Factor-beta Type I - metabolism; Receptors, Antigen, T-Cell - immunology; Research & development; Signal Transduction - immunology; Signaling; Statistical analysis; Studies; T cell activation; T cell quiescence; T cell receptors; TCR signaling; TGF-β; Transcription factors; Transforming growth factor; Transforming Growth Factor beta1 - biosynthesis; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b; China; signaling; T cell activation; receptor I downregulation; autoimmunity; NF-kB; TCR signaling; T cell quiescence; TGF-β; CARD11; IL-6
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2018.03.025

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. [Display omitted] •Naive T cells show active TGF-β signaling and TβR expression•Strong TCR stimulation decreases TβRI and TGF-β signaling by CARD11 and NF-κB•Overexpression of TβRI suppresses T cell response and autoimmunity•TβRI expression is reduced in naive T cells of SLE patients It is unclear how quiescence is enforced in naive T cells, yet activation is allowed. Tu et al. show that TGF-β signaling maintains T cell quiescence. Strong TCR stimuli reduce TβRI expression and consequently abolish TGF-β signaling in T cells. TCR-mediated TβRI downregulation acts as a “third criterion” to fully activate T cells in addition to the “two-signal” model.