{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:24Z","timestamp":1792790364499,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,24]]},"group-title":"Immunology","reference-count":76,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["T32DK007074-47"],"award-info":[{"award-number":["T32DK007074-47"]}]},{"name":"National Institutes of Health","award":["T32GM007183"],"award-info":[{"award-number":["T32GM007183"]}]},{"name":"National Institutes of Health","award":["RC2DK133947"],"award-info":[{"award-number":["RC2DK133947"]}]},{"name":"National Institutes of Health","award":["R01DK067180"],"award-info":[{"award-number":["R01DK067180"]}]},{"name":"National Institutes of Health","award":["R35GM138150"],"award-info":[{"award-number":["R35GM138150"]}]},{"name":"U.S. National Science Foundation","award":["2140001"],"award-info":[{"award-number":["2140001"]}],"id":[{"id":"https:\/\/ror.org\/021nxhr62","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Wellcome Trust","award":["100326\/Z\/12\/Z"],"award-info":[{"award-number":["100326\/Z\/12\/Z"]}],"id":[{"id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Australian Research Council","award":["DP230102073"],"award-info":[{"award-number":["DP230102073"]}],"id":[{"id":"https:\/\/ror.org\/05mmh0f86","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,24]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>Intestinal V\u03b34 \u03b3\u03b4 intraepithelial lymphocytes (IELs) persistently bind the constitutively expressed epithelial ligand BTNL3\/8 through germline-encoded T cell receptor (TCR) determinants. While they resemble innate-like T cells such as NKT cells, unlike these populations, V\u03b34 IELs encounter ligand only after thymic development. Moreover, unlike conventional \u03b1\u03b2 T cells, V\u03b34 IELs sustain persistent physiological ligand engagement without becoming exhausted. Here, using biophysical, functional, and multimodal single-cell approaches, we show how V\u03b34 IELs address this challenge. While germline-encoded TCR regions broadly mediate BTNL3 recognition, productive activation requires additional non-germline TCR features that license responsiveness to BTNL3\/8 and enable local selection in the gut. Rather than driving exhaustion, BTNL3\/8 reactivity directly promotes expression of an NK-like program marked by adaptor molecules that license innate-like signaling in healthy tissue. These findings reveal how combined innate and adaptive features of the \u03b3\u03b4TCR enable durable tissue specialization under conditions of persistent physiological ligand engagement.<\/jats:p>","DOI":"10.64898\/2026.09.17.751481","type":"posted-content","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:45:16Z","timestamp":1790282716000},"source":"Crossref","is-referenced-by-count":0,"title":["Adaptive-like features of the \u03b3\u03b4 TCR couple chronic BTNL recognition to NK-like tissue immunity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1308-8788","authenticated-orcid":false,"given":"Benjamin D","family":"McDonald","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5049-7452","authenticated-orcid":false,"given":"Hope 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Medicine, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9416-2737","authenticated-orcid":false,"given":"David A","family":"Price","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK"},{"name":"Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narutoshi","family":"Hibino","sequence":"additional","affiliation":[{"name":"Section of Pediatric Cardiac Surgery, Comer\u2019s Children\u2019s Hospital, University of Chicago, Chicago, IL, USA"},{"name":"Section of Pediatric Cardiac Surgery, Advocate Children\u2019s Hospital, Advocate Children\u2019s Heart Institute, Oak Lawn, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew S","family":"Koh","sequence":"additional","affiliation":[{"name":"Committee on Immunology, 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