{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T04:11:01Z","timestamp":1777867861498,"version":"3.51.4"},"posted":{"date-parts":[[2026,4,27]]},"group-title":"Immunology","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NIH","award":["R01AI123323"],"award-info":[{"award-number":["R01AI123323"]}]},{"name":"NIH","award":["K12HD047349"],"award-info":[{"award-number":["K12HD047349"]}]},{"name":"NIH","award":["K08HL157562"],"award-info":[{"award-number":["K08HL157562"]}]},{"name":"NIH","award":["R21AI130797"],"award-info":[{"award-number":["R21AI130797"]}]},{"name":"NIH","award":["R01HL169265"],"award-info":[{"award-number":["R01HL169265"]}]},{"name":"NIH","award":["P30 CA015704"],"award-info":[{"award-number":["P30 CA015704"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\u03b3\u03b4 T cells provide mucosal defense against infection while also contributing to tissue repair. However, data regarding the effect of the human lung environment on \u03b3\u03b4 T cell functionality remains limited. To address whether lung inflammation impacts \u03b3\u03b4 T cell functionality, we analyzed lung and matched hilar lymph node (LN) tissue from deceased donors and patients with interstitial lung disease (ILD). We performed high-parameter spectral flow cytometry to examine the expression pattern of phenotypic biomarkers and assess ex vivo function. We identified lung-specific enrichment of \u03b3\u03b4 T cells with an effector memory phenotype relative to matched regional LN. We then used an ex vivo stimulation approach to interrogate the capacity to protect against infection (granzyme B [GzmB], interferon-\u03b3 [IFN\u03b3] and tumor necrosis factor [TNF\u03b1]) and promote epithelial cell proliferation (amphiregulin [AREG]). We found that \u03b3\u03b4 T cells in lung and LN from deceased donors had similar functional properties. While \u03b3\u03b4 T cell populations from ILD lungs largely maintained cytokine production capacity, expression was diminished relative to LN counterparts. Importantly, lung \u03b3\u03b4 T cells maintained polyfunctional GzmB, IFN\u03b3 and TNF\u03b1 expression across cohorts. Overall, we report human lung \u03b3\u03b4 T cells are regionally distinct with conserved functionality in a fibrotic environment.<\/jats:p>","DOI":"10.64898\/2026.04.23.720435","type":"posted-content","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:50:18Z","timestamp":1777337418000},"source":"Crossref","is-referenced-by-count":0,"title":["Human lung \u03b3\u03b4 T cells maintain functionality during inflammatory lung disease"],"prefix":"10.64898","author":[{"given":"Alexis","family":"Taber","sequence":"first","affiliation":[{"name":"Fred Hutchinson Cancer Center, Vaccine and Infectious Disease Division, Seattle, WA, 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie","family":"Frutoso","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center, Vaccine and Infectious Disease Division, Seattle, WA, 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Potchen","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center, Vaccine and Infectious Disease Division, Seattle, WA, 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda L.","family":"Koehne","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center, Experimental Histopathology, Seattle, WA, 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chelsea","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, 98104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric D.","family":"Morrell","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, 98104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0685-9321","authenticated-orcid":false,"given":"Martin","family":"Prlic","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center, Vaccine and Infectious Disease Division, Seattle, WA, 98109, USA"},{"name":"Departments of Global Health and Immunology, University of Washington, Seattle, WA, 98195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shelton W.","family":"Wright","sequence":"additional","affiliation":[{"name":"Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington, Seattle, WA, 98104"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026043004051846000_2026.04.23.720435v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-00477-9"},{"key":"2026043004051846000_2026.04.23.720435v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-011-0697-3"},{"key":"2026043004051846000_2026.04.23.720435v1.3","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12764"},{"key":"2026043004051846000_2026.04.23.720435v1.4","doi-asserted-by":"crossref","unstructured":"Hu Y , Hu Q , Li Y , Lu L , Xiang Z , Yin Z , et al. \u03b3\u03b4 T cells: origin and fate, subsets, diseases and immunotherapy. 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