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However, how IFN-I\/III expression is controlled in adaptive cells is poorly understood. Here, we identify a transcriptional rheostat orchestrated by RELA that confers human T cells with innate-like abilities to produce IFN-I\/III. Despite intact cGAS-STING signaling, IFN-I\/III responses are stunted in CD4+ T cells compared with dendritic cells or macrophages. We find that lysine residues in RELA tune the IFN-I\/III response at baseline and in response to STING stimulation in CD4+ T cells. This response requires positive feedback driven by cGAS and IRF7 expression. By combining RELA with IRF3 and DNA demethylation, IFN-I\/III production in CD4+ T cells reaches levels observed in dendritic cells. IFN-I\/III production provides self-protection of CD4+ T cells against HIV infection and enhances the elimination of tumor cells by CAR T cells. Therefore, innate-like functions can be tuned and leveraged in human T cells.<\/jats:p>","DOI":"10.1084\/jem.20220666","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T02:20:56Z","timestamp":1673403656000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["RELA tunes innate-like interferon I\/III responses in human T cells"],"prefix":"10.1084","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7805-6341","authenticated-orcid":true,"given":"Nadia","family":"Jeremiah","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04t0gwh46","id-type":"ROR","asserted-by":"publisher"}],"name":"Institut Curie 1 , Paris, France"},{"name":", Paris Sciences et Lettres Research University, INSERM U932 1 , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5134-0860","authenticated-orcid":true,"given":"Hermine","family":"Ferran","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04t0gwh46","id-type":"ROR","asserted-by":"publisher"}],"name":"Institut Curie 1 , Paris, France"},{"name":", Paris Sciences et Lettres Research University, INSERM U932 1 , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9691-6889","authenticated-orcid":true,"given":"Konstantina","family":"Antoniadou","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04t0gwh46","id-type":"ROR","asserted-by":"publisher"}],"name":"Institut Curie 1 , Paris, France"},{"name":", Paris Sciences et Lettres Research University, INSERM U932 1 , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4714-9526","authenticated-orcid":true,"given":"Kevin","family":"De Azevedo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04t0gwh46","id-type":"ROR","asserted-by":"publisher"}],"name":"Institut Curie 1 , Paris, France"},{"name":", Paris Sciences et Lettres Research University, INSERM U932 1 , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4119-7009","authenticated-orcid":true,"given":"Jovan","family":"Nikolic","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04t0gwh46","id-type":"ROR","asserted-by":"publisher"}],"name":"Institut Curie 1 , Paris, France"},{"name":", Paris Sciences et Lettres Research University, INSERM U932 1 , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3555-6247","authenticated-orcid":true,"given":"Mathieu","family":"Maurin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04t0gwh46","id-type":"ROR","asserted-by":"publisher"}],"name":"Institut Curie 1 , Paris, France"},{"name":", Paris Sciences et Lettres Research University, INSERM U932 1 , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2655-0129","authenticated-orcid":true,"given":"Philippe","family":"Benaroch","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04t0gwh46","id-type":"ROR","asserted-by":"publisher"}],"name":"Institut Curie 1 , Paris, France"},{"name":", Paris Sciences et Lettres Research University, INSERM U932 1 , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1481-4430","authenticated-orcid":true,"given":"Nicolas","family":"Manel","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04t0gwh46","id-type":"ROR","asserted-by":"publisher"}],"name":"Institut Curie 1 , Paris, France"},{"name":", Paris Sciences et Lettres Research University, INSERM U932 1 , Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2023,2,23]]},"reference":[{"key":"2023030712142053600_","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1038\/s42255-019-0081-4","article-title":"Metabolic plasticity of HIV-specific CD8+ T cells is associated with enhanced antiviral potential and natural control of HIV-1 infection","volume":"1","author":"Angin","year":"2019","journal-title":"Nat. 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