{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:39:17Z","timestamp":1768505957853,"version":"3.49.0"},"posted":{"date-parts":[[2023,9,3]]},"group-title":"Immunology","reference-count":65,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2023,9,3]],"date-time":"2023-09-03T00:00:00Z","timestamp":1693699200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Natural intraepithelial T lymphocytes (T-IELs) are innate-like, intestine-resident T cells essential for gut homeostasis. These cells express self-reactive T cell antigen receptors (TCRs) due to thymic agonist selection, but they do not cause autoimmunity. The mechanism underlying natural T-IELs tolerance in the gut is unclear. Using TCR reporter mouse models and phosphoproteomics, we demonstrate that TCR signaling is intrinsically suppressed in natural T-IELs. We discover that this suppression occurs post-selection in the thymus through altered expression of TCR signalosome components, a mechanism we term RePrESS (Rewiring of Proximal Elements of TCR Signalosome for Suppression). RePrESS is evolutionarily conserved and also found in autoreactive innate-like T cells from skin, breast and prostate. In coeliac disease, tolerance breakdown is associated with loss of RePrESS in natural T-IELs. Our findings reveal a distinct, conserved mechanism of tolerance involving TCR signaling rewiring, with implications for understanding barrier tissue homeostasis and autoimmune disease.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One sentence summary<\/jats:title>\n                  <jats:p>Autoreactive innate-like T lymphocytes are developmentally suppressed by rewiring of the T cell antigen receptor signaling pathway to maintain tolerance.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.09.01.555859","type":"posted-content","created":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T00:50:13Z","timestamp":1693788613000},"source":"Crossref","is-referenced-by-count":1,"title":["Conserved developmental rewiring of the TCR signalosome drives tolerance in innate-like lymphocytes"],"prefix":"10.64898","author":[{"given":"Amanpreet 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