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While CD4<jats:sup>+<\/jats:sup> T cells, primarily Th1 and Th17 subsets, drive disease pathogenesis, the exact function of CD8<jats:sup>+<\/jats:sup> T cells remains unclear. We previously demonstrated that adoptively transferred myelin-reactive CD8<jats:sup>+<\/jats:sup> T cells (PLP-CD8) prevent EAE induction and suppress ongoing disease through the engagement of MHC Class-I in recipient mice. Here, we show that PLP-CD8 induce regulatory changes in both subsets of conventional dendritic cells (cDC1 and CD11b<jats:sup>+<\/jats:sup> cDC) in vivo and in vitro. Adoptively transferred PLP-CD8 promoted both cDC subsets to adopt a mature and regulatory phenotype with an anti-inflammatory cytokine profile and a reduced capacity to support CD4<jats:sup>+<\/jats:sup> T cell proliferation. In vitro, PLP-CD8 induced similar phenotypic changes in both cDC subsets in an antigen-specific, dose-dependent manner. PLP-CD8 directly interacted with cDC1 and indirectly influenced CD11b<jats:sup>+<\/jats:sup> cDC through paracrine signaling. Notably, direct interaction with PLP-CD8 had detrimental effects on CD11b<jats:sup>+<\/jats:sup> cDC. Single-cell RNA sequencing revealed upregulation of key immunoregulatory genes, such as <jats:italic>Foxo3<\/jats:italic>, in both cDC subsets with enrichment of pathways involved in immune regulation and T cell differentiation. Our study highlights a novel mechanism in which myelin-reactive CD8<jats:sup>+<\/jats:sup> T cells directly interact with cDC1 and modulate CD11b<jats:sup>+<\/jats:sup> cDC through paracrine mechanisms to induce mature, regulatory dendritic cells, which leads to inhibited CD4<jats:sup>+<\/jats:sup> T cell responses and reduced EAE pathogenesis.<\/jats:p>","DOI":"10.1186\/s12974-025-03377-8","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T10:49:10Z","timestamp":1740739750000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Myelin-reactive CD8+ T cells influence conventional dendritic cell subsets towards a mature and regulatory phenotype in experimental autoimmune encephalomyelitis"],"prefix":"10.1186","volume":"22","author":[{"given":"Mohit","family":"Upadhye","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Connor R.","family":"Wilhelm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai J.","family":"Rogers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chakrapani","family":"Vemulawada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Borcherding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander W.","family":"Boyden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin L.","family":"Legge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6867-6950","authenticated-orcid":false,"given":"Nitin J.","family":"Karandikar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,2,28]]},"reference":[{"key":"3377_CR1","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1001\/jamaneurol.2023.1135","volume":"80","author":"M Hittle","year":"2023","unstructured":"Hittle M, Culpepper WJ, Langer-Gould A, Marrie RA, Cutter GR, Kaye WE, Wagner L, Topol B, LaRocca NG, Nelson LM, et al. 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