{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T19:41:41Z","timestamp":1792870901532,"version":"4.5.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Lymphedema, a progressive condition involving unresolved swelling and inflammation, affects as many as 1 in 1000 Americans. Although CD4+ T cells are implicated in the chronic inflammatory process, antigen-specific responses are understudied.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using high-throughput sequencing, we studied the T cell receptors (TCRs) of CD4+ T cells in paired normal and lymphedema skin biopsies of 11 patients. We also employed <jats:italic>in vitro<\/jats:italic> studies using human samples and cells from a lymphedema mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Target epitopes of the TCRs, including the antigen insulin, were identified. Clonality was significantly higher in lymphedema samples than in controls, both in human samples and a mouse model of the disease. <jats:italic>In vitro<\/jats:italic> studies using human samples and a lymphedema mouse model demonstrated increased activated memory T cell responses specific to the antigen insulin compared with the control.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our study highlights an oligoclonal expansion of CD4+ T cells in lymphedema and supports insulin as a probable antigen driving T cell responses. These findings can help inform more precise therapeutic targets for the development of better therapies and preventative tools to combat lymphedema progression.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1620571","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T05:32:05Z","timestamp":1754026325000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Lymphedema pathogenesis involves antigen-driven expansion of CD4+ T cells in skin"],"prefix":"10.3389","volume":"16","author":[{"given":"Adana-Christine","family":"Campbell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annica R.","family":"Stull-Lane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Eun","family":"Baik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ananta","family":"Sarker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyeon","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gopika","family":"Ashokan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeung Ju","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bracha L.","family":"Pollack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradhi","family":"Pakkerakari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yollanda Franco","family":"Parisotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arielle","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrysothemis C.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Babak J.","family":"Mehrara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghu P.","family":"Kataru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/PRS.0000000000009866","article-title":"The vicious circle of stasis, inflammation, and fibrosis in lymphedema","volume":"151","author":"Brown","year":"2023","journal-title":"Plast Reconstr Surg"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/PRS.0000000000007783","article-title":"Surgical treatment of lymphedema: a systematic review and meta-analysis of controlled trials. 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