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There are at least four distinct Th cell subsets (Th1, Th2, Th17, and inducible T\u2010regulatory cells), each of which has specialized functions to control immune responses. Each of these cell types emerge from naive <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>4<jats:sup>+<\/jats:sup> T cells after encounter with foreign antigens presented by dendritic cells (<jats:styled-content style=\"fixed-case\">DC<\/jats:styled-content>s). Each Th cell subset expresses a unique set of transcription factors and produces hallmark cytokines. Both T\u2010cell receptor (<jats:styled-content style=\"fixed-case\">TCR<\/jats:styled-content>)\u2010mediated stimulation and the cytokine environment created by activated <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>4<jats:sup>+<\/jats:sup> T cells themselves, by \u2018partner\u2019 <jats:styled-content style=\"fixed-case\">DC<\/jats:styled-content>s, and\/or other cell types during the course of differentiation, play an important role in the fate decisions toward distinct Th subsets. Here, we review how <jats:styled-content style=\"fixed-case\">TCR<\/jats:styled-content>\u2010mediated signals in collaboration with the cytokine environment influence the fate decisions of naive <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>4<jats:sup>+<\/jats:sup> T cells toward distinct Th subsets at the early stages of activation. We also discuss the roles of <jats:styled-content style=\"fixed-case\">TCR<\/jats:styled-content>\u2010proximal signaling intermediates and of the Notch pathway in regulating the differentiation to distinct Th phenotypes.<\/jats:p>","DOI":"10.1111\/imr.12032","type":"journal-article","created":{"date-parts":[[2013,2,18]],"date-time":"2013-02-18T20:17:31Z","timestamp":1361218651000},"page":"12-23","source":"Crossref","is-referenced-by-count":256,"title":["Early signaling events that underlie fate decisions of naive <scp>CD<\/scp>4<sup>+<\/sup> T cells toward distinct T\u2010helper cell subsets"],"prefix":"10.1111","volume":"252","author":[{"given":"Hidehiro","family":"Yamane","sequence":"first","affiliation":[{"name":"Cytokine Biology Unit, Laboratory of Immunology National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD USA"}]},{"given":"William E.","family":"Paul","sequence":"additional","affiliation":[{"name":"Cytokine Biology Unit, Laboratory 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