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Recent work identified memory-like CXCR5+ TCF1+ CD8+ T cells that sustain T cell responses during persistent infection and proliferate upon anti-PD1 treatment. Approaches to expand these cells are sought. We show that blockade of interferon type 1 (IFN-I) receptor leads to CXCR5+ CD8+ T cell expansion in an IL-27\u2013 and STAT1-dependent manner. IFNAR1 blockade promoted accelerated cell division and retention of TCF1 in virus-specific CD8+ T cells. We found that CD8+ T cell\u2013intrinsic IL-27 signaling safeguards the ability of TCF1hi cells to maintain proliferation and avoid terminal differentiation or programmed cell death. Mechanistically, IL-27 endowed rapidly dividing cells with IRF1, a transcription factor that was required for sustained division in a cell-intrinsic manner. These findings reveal that IL-27 opposes IFN-I to uncouple effector differentiation from cell division and suggest that IL-27 signaling could be exploited to augment self-renewing T cells in chronic infections and cancer.<\/jats:p>","DOI":"10.1084\/jem.20190173","type":"journal-article","created":{"date-parts":[[2019,6,4]],"date-time":"2019-06-04T18:45:30Z","timestamp":1559673930000},"page":"1791-1808","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":73,"title":["IL-27 promotes the expansion of self-renewing CD8+ T cells in persistent viral infection"],"prefix":"10.1084","volume":"216","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1312-5457","authenticated-orcid":true,"given":"Zhe","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8135-856X","authenticated-orcid":true,"given":"Jaroslav","family":"Zak","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaraphorn","family":"Pratumchai","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 1"},{"name":"Department of Chemical Immunology, Leiden University Medical Center, Leiden, Netherlands 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namir","family":"Shaabani","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent F.","family":"Vartabedian","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nhan","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuoqi","family":"Wu","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8754-3208","authenticated-orcid":true,"given":"Changchun","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8280-8887","authenticated-orcid":true,"given":"John R.","family":"Teijaro","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2019,6,4]]},"reference":[{"key":"2023072604453143200_bib1","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. 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