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The commensal Corynebacterium mastitidis (C. mast) 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 C. mast\u2013responsive subset in the conjunctiva and uncover its unique activation requirements. We demonstrate that V\u03b36 cells require both extrinsic (via dendritic cells) and intrinsic TLR2 stimulation for optimal IL-17A response. Mechanistically, intrinsic TLR2 signaling was associated with epigenetic changes and enhanced expression of genes involved in fatty acid oxidation to support Il17a transcription. We identify a 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.<\/jats:p>","DOI":"10.1084\/jem.20251046","type":"journal-article","created":{"date-parts":[[2025,8,16]],"date-time":"2025-08-16T06:20:46Z","timestamp":1755325246000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["TLR2 supports \u03b3\u03b4 T cell IL-17A response to ocular surface commensals by metabolic reprogramming"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8399-9131","authenticated-orcid":true,"given":"Wenjie","family":"Zhu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}],"name":"National Eye Institute, National Institutes of Health 1 Laboratory of Immunology, , Bethesda, MD,","place":["USA"]},{"name":"Zhongshan 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