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CD1c-autoreactive T-cells, which recognise self-lipids presented by the antigen-presenting molecule CD1c, are frequent in human blood but their role during infection remains unclear. Here, we investigate how CD1c-expressing antigen-presenting cells (APCs) and Mtb infection shape CD1c-autoreactive T-cell responses using engineered human APC systems, complemented by single-cell transcriptomic profiling to define the ex vivo phenotypic landscape of these T-cells. CD1c is present within human TB granulomas, whereas Mtb down-modulates CD1c expression on infected APCs, consistent with an immune evasion strategy. CD1c-autoreactive T-cells respond more strongly to Mtb-infected CD1c\n                    <jats:sup>+<\/jats:sup>\n                    APCs than to uninfected cells, exhibiting enhanced activation, cytotoxicity, and diverse cytokine secretion via CD1c-dependent recognition. Under in vitro conditions, these T-cells reduce relative Mtb burden in infected phagocytes. Single-cell RNA sequencing reveals cytotoxic effector-memory programmes and expression of antimicrobial molecules, providing a mechanistic basis for these responses. Together, these findings define a human CD1c-restricted T-cell response to Mtb-infected APCs and identify autoreactive CD1c-restricted T-cells as a candidate cellular axis for lipid-directed immunity in TB.\n                  <\/jats:p>","DOI":"10.7554\/elife.110341","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T14:30:15Z","timestamp":1774881015000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.110341","source":"Crossref","is-referenced-by-count":0,"title":["Human CD1c-autoreactive T-cells recognise Mycobacterium tuberculosis-infected antigen-presenting cells and display cytotoxic effector programmes"],"prefix":"10.7554","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2509-7171","authenticated-orcid":true,"given":"Matthew","family":"Milton","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01ryk1543","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Clinical and Experimental Sciences, NIHR 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