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CRACR2A has been linked to human diseases in numerous genome-wide association studies and was shown to be one of the most sensitive targets of the widely used statin drugs. However, the physiological role of CRACR2A in T cell functions remains unknown. In this study, using transgenic mice for tissue-specific deletion, we show that CRACR2A promotes Th1 responses and effector function of Th17 cells. CRACR2A was abundantly expressed in Th1 and Th17 cells. In vitro, deficiency of CRACR2A decreased Th1 differentiation under nonpolarizing conditions, whereas the presence of polarizing cytokines compensated this defect. Transcript analysis showed that weakened TCR signaling by deficiency of CRACR2A failed to promote Th1 transcriptional program. In vivo, conditional deletion of CRACR2A in T cells alleviated Th1 responses to acute lymphocytic choriomeningitis virus infection and imparted resistance to experimental autoimmune encephalomyelitis. Analysis of CNS from experimental autoimmune encephalomyelitis\u2013induced mice showed impaired effector functions of both Th1 and Th17 cell types, which correlated with decreased pathogenicity. Collectively, our findings demonstrate the requirement of CRACR2A-mediated TCR signaling in Th1 responses as well as pathogenic conversion of Th17 cells, which occurs at the site of inflammation.<\/jats:p>","DOI":"10.4049\/jimmunol.1800659","type":"journal-article","created":{"date-parts":[[2018,7,9]],"date-time":"2018-07-09T13:44:41Z","timestamp":1531143881000},"page":"1174-1185","source":"Crossref","is-referenced-by-count":24,"title":["CRACR2A-Mediated TCR Signaling Promotes Local Effector Th1 and Th17 Responses"],"prefix":"10.1093","volume":"201","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8921-2832","authenticated-orcid":false,"given":"Jin Seok","family":"Woo","sequence":"first","affiliation":[{"name":"Department of Physiology, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3034-095X","authenticated-orcid":false,"given":"Sonal","family":"Srikanth","sequence":"additional","affiliation":[{"name":"Department of Physiology, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6872-5583","authenticated-orcid":false,"given":"Kyun-Do","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Elsaesser","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Center, University Health Network , Toronto, Ontario M5G 2M9 ,","place":["Canada"]},{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5G 2M9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell and Developmental Biology, University of California , Los Angeles, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Pellegrini","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell and Developmental Biology, University of California , Los Angeles, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G","family":"Brooks","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Center, University Health Network , Toronto, Ontario M5G 2M9 ,","place":["Canada"]},{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5G 2M9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1896-6666","authenticated-orcid":false,"given":"Zuoming","family":"Sun","sequence":"additional","affiliation":[{"name":"Division of Molecular Immunology, Beckman Research Institute of the City of Hope , Duarte, CA 91010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yousang","family":"Gwack","sequence":"additional","affiliation":[{"name":"Department of Physiology, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,8,15]]},"reference":[{"key":"2025030417571647800_r1","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1002\/mgg3.168","article-title":"Genetic analysis of nonalcoholic fatty liver disease within a Caribbean-Hispanic population","volume":"3","author":"Edelman","year":"2015","journal-title":"Mol. 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