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Although activation of the NF-\u03baB signaling pathway has long been implicated in Tconv biology, the cell-autonomous roles of the separate NF-\u03baB transcription-factor subunits are unknown. Here, we dissected the contributions of the canonical NF-\u03baB subunits RelA and c-Rel to Tconv function. RelA, rather than c-Rel, regulated Tconv activation and cytokine production at steady-state and was required for polarization toward the TH17 lineage in vitro. Accordingly, RelA-deficient mice were fully protected against neuroinflammation in a model of multiple sclerosis due to defective transition to a pathogenic TH17 gene-expression program. Conversely, Tconv-restricted ablation of c-Rel impaired their function in the microenvironment of transplanted tumors, resulting in enhanced cancer burden. Moreover, Tconv required c-Rel for the response to PD-1-blockade therapy. Our data reveal distinct roles for canonical NF-\u03baB subunits in different disease contexts, paving the way for subunit-targeted immunotherapies.<\/jats:p>","DOI":"10.1084\/jem.20231348","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T02:21:13Z","timestamp":1710382873000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":23,"title":["NF-\u03baB subunits RelA and c-Rel selectively control CD4+ T cell function in multiple sclerosis and cancer"],"prefix":"10.1084","volume":"221","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8861-9523","authenticated-orcid":true,"given":"Guilhem","family":"Lalle","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02mgw3155","id-type":"ROR","asserted-by":"publisher"}],"name":"Cancer Research Center of Lyon, Labex DEV2CAN, Institut Convergence Plascan, Centre L\u00e9on B\u00e9rard, UMR INSERM 1052, CNRS 5286, Universit\u00e9 Claude 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