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Using adoptive transfer of virus\u2010specific <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>4 T cells, we show that naive <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>4 T cells undergo substantial expansion following infection, but can induce lethal <jats:styled-content style=\"fixed-case\">T<\/jats:styled-content> helper type 1\u2010driven inflammation. In contrast, memory <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>4 T cells exhibit a biased proliferation of T follicular helper cell subsets and were able to improve adaptive immune responses in the context of minimal tissue damage. Our analyses revealed that type I interferon regulates the expansion of primary <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>4 T cells, but does not seem to play a critical role in regulating the expansion of secondary <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>4 T cells. Strikingly, blockade of type I interferon abrogated lethal inflammation by primary <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>4 T cells following viral infection, despite that this treatment increased the numbers of primary <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>4 T\u2010cell responses. Altogether, these data demonstrate important aspects of how primary and secondary <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>4 T cells are regulated <jats:italic>in\u00a0vivo<\/jats:italic>, and how they contribute to immune protection and immunopathology. These findings are important for rational vaccine design and for improving adoptive T\u2010cell therapies against persistent antigens.<\/jats:p>","DOI":"10.1111\/imm.12771","type":"journal-article","created":{"date-parts":[[2017,6,5]],"date-time":"2017-06-05T22:50:45Z","timestamp":1496703045000},"page":"328-343","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Regulation of <scp>CD<\/scp>4 T cells and their effects on immunopathological inflammation following viral infection"],"prefix":"10.1111","volume":"152","author":[{"given":"Mitra","family":"Bhattacharyya","sequence":"first","affiliation":[{"name":"Department of Microbiology\u2010Immunology Feinberg School of Medicine Northwestern University Chicago IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Madden","sequence":"additional","affiliation":[{"name":"Department of Microbiology\u2010Immunology Feinberg School of Medicine 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