{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T17:05:22Z","timestamp":1776013522850,"version":"3.50.1"},"posted":{"date-parts":[[2024,4,1]]},"group-title":"Immunology","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"crossref","award":["EY000184"],"award-info":[{"award-number":["EY000184"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  The ocular surface is a mucosal barrier tissue colonized by commensal microbes, which tune local immunity by eliciting IL-17 from conjunctival \u03b3\u03b4 T cells to prevent pathogenic infection. The commensal\n                  <jats:italic>Corynebacterium mastitidis<\/jats:italic>\n                  (\n                  <jats:italic>C. mast<\/jats:italic>\n                  ) elicits protective IL-17 responses from conjunctival V\u03b34 T cells through a combination of \u03b3\u03b4 TCR ligation and IL-1 signaling. Here, we identify V\u03b36 T cells as a major\n                  <jats:italic>C. mast<\/jats:italic>\n                  -responsive subset in the conjunctiva and uncover its unique activation requirements. We demonstrate that V\u03b36 cells require not only extrinsic (via dendritic cells) but also intrinsic TLR2 stimulation for optimal IL-17A response. Mechanistically, intrinsic TLR2 signaling was associated with epigenetic changes and enhanced expression of genes responsible for metabolic shift to fatty acid oxidation to support\n                  <jats:italic>Il17a<\/jats:italic>\n                  transcription. We identify one key transcription factor, I\u03baB\u03b6, which is upregulated by TLR2 stimulation and is essential for this program. Our study highlights the importance of intrinsic TLR2 signaling in driving metabolic reprogramming and production of IL-17A in microbiome-specific mucosal \u03b3\u03b4 T cells.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:p>\n                    Ocular commensal\n                    <jats:italic>Corynebacterium mastitidis<\/jats:italic>\n                    (\n                    <jats:italic>C. mast<\/jats:italic>\n                    ) induces IL-17 responses from \u03b3\u03b4 T cells by activating TLR2 signaling. \u03b3\u03b4 T cell-intrinsic TLR2 stimulation can increase\n                    <jats:italic>Il17a<\/jats:italic>\n                    transcription and promote fatty acid oxidation, favoring \u03b3\u03b4 T cell IL-17A responses.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"simple\">\n                    <jats:list-item>\n                      <jats:label>(1)<\/jats:label>\n                      <jats:p>\n                        V\u03b36 T cells are a major\n                        <jats:italic>C. mast<\/jats:italic>\n                        -responsive subset in the conjunctiva\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:label>(2)<\/jats:label>\n                      <jats:p>TLR2-deficient mice exhibit reduced \u03b3\u03b4 T cell responses to ocular commensal bacteria.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:label>(3)<\/jats:label>\n                      <jats:p>\u03b3\u03b4 T cell-intrinsic TLR2 deficiency causes defects of fatty acid oxidation and IL-17A production in a \u03b3\u03b4 subset-specific manner.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:label>(4)<\/jats:label>\n                      <jats:p>The transcription factor, I\u03baB\u03b6 is upregulated by TLR2 stimulation and supports \u03b3\u03b4 IL-17A production through fatty acid oxidation.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Abstract Figure<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"587519v2_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2024.04.01.587519","type":"posted-content","created":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T23:15:18Z","timestamp":1712013318000},"source":"Crossref","is-referenced-by-count":1,"title":["TLR2 Supports \u03b3\u03b4 T cell IL-17A Response to ocular surface commensals by Metabolic Reprogramming"],"prefix":"10.64898","author":[{"given":"Wenjie","family":"Zhu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vijayaraj","family":"Nagarajan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akriti","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zixuan","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary J.","family":"Mattapallil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingyos","family":"Jittayasothorn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reiko","family":"Horai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasmine","family":"Belkaid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Constantinides","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony J. 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