LAUSR

SUMMARY 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 &bgr; (TGF‐&bgr;) signaling was present in naive T cells, and T cell receptor (TCR) engagement reduced TGF‐&bgr; signaling during T cell activation by downregulating TGF‐&bgr; type 1 receptor (T&bgr;RI) through activation of caspase recruitment domain‐containing protein 11 (CARD11) and nuclear factor &kgr;B (NF‐&kgr;B). TGF‐&bgr; prevented TCR‐mediated T&bgr;RI downregulation, but this was abrogated by interleukin‐6 (IL‐6). Mitigation of TCR‐mediated T&bgr;RI downregulation through overexpression of T&bgr;RI in naive and activated T cells rendered T cells less responsive and suppressed autoimmunity. Naive T cells in autoimmune patients exhibited reduced T&bgr;RI expression and increased TCR‐driven proliferation compared to healthy subjects. Thus, TCR‐mediated regulation of T&bgr;RI‐TGF‐&bgr; signaling acts as a crucial criterion to determine T cell quiescence and activation. Graphical Abstract Figure. No caption available. HighlightsNaive T cells show active TGF‐&bgr; signaling and T&bgr;R expressionStrong TCR stimulation decreases T&bgr;RI and TGF‐&bgr; signaling by CARD11 and NF‐&kgr;BOverexpression of T&bgr;RI suppresses T cell response and autoimmunityT&bgr;RI expression is reduced in naive T cells of SLE patients In Brief It is unclear how quiescence is enforced in naive T cells, yet activation is allowed. Tu et al. show that TGF‐&bgr; signaling maintains T cell quiescence. Strong TCR stimuli reduce T&bgr;RI expression and consequently abolish TGF‐&bgr; signaling in T cells. TCR‐mediated T&bgr;RI downregulation acts as a “third criterion” to fully activate T cells in addition to the “two‐signal” model.