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Using a persistent lymphocytic choriomeningitis virus infection model, we showed in this study that although VAD did not alter innate type I IFN production, infected VAD mice had hyperactive, virus-specific T cell responses at both the acute and contraction stages, showing significantly decreased PD-1 but increased cytokine (IFN-\u03b3, TNF-\u03b1, and IL-2) expression by T cells. Compared with control mice, VAD mice displayed excessive inflammation and more severe liver pathology, with increased death during persistent infection. Of note, supplements of all-trans retinoic acid (RA), one of the important metabolites of vitamin A, downregulated hyperactive T cell responses and rescued the persistently infected VAD mice. By using adoptive transfer of splenocytes, we found that the environmental vitamin A or its metabolites acted as rheostats modulating antiviral T cells. The analyses of T cell transcriptional factors and signaling pathways revealed the possible mechanisms of RA, as its supplements inhibited the abundance of NFATc1 (NFAT 1), a key regulator for T cell activation. Also, following CD3\/CD28 cross-linking stimulation, RA negatively regulated the TCR-proximal signaling in T cells, via decreased phosphorylation of Zap70 and its downstream signals, including phosphorylated AKT, p38, ERK, and S6, respectively. Together, our data reveal VAD-mediated alterations in antiviral T cell responses and highlight the potential utility of RA for modulating excessive immune responses and tissue injury in infectious diseases.<\/jats:p>","DOI":"10.4049\/jimmunol.1901091","type":"journal-article","created":{"date-parts":[[2020,4,13]],"date-time":"2020-04-13T15:45:13Z","timestamp":1586792713000},"page":"2984-2994","source":"Crossref","is-referenced-by-count":24,"title":["Retinoic Acid Modulates Hyperactive T Cell Responses and Protects Vitamin A\u2013Deficient Mice against Persistent Lymphocytic Choriomeningitis Virus Infection"],"prefix":"10.1093","volume":"204","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9557-1847","authenticated-orcid":false,"given":"Yuejin","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch , Galveston, TX 77555"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panpan","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch , Galveston, TX 77555"},{"name":"Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University , Changsha, Hunan 410011 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch , Galveston, TX 77555"},{"name":"Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University , Changsha, Hunan 410011 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch , Galveston, TX 77555"},{"name":"Department of Histology and Embryology, Guangdong Medical University , Zhanjiang, Guangdong 524000 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuliang","family":"Jie","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Texas MD Anderson Cancer Center , Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3370-3434","authenticated-orcid":false,"given":"Lynn","family":"Soong","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch , Galveston, TX 77555"},{"name":"Department of Pathology, University of Texas Medical Branch , Galveston, TX 77555"},{"name":"Institute for Human Infections and Immunity, University of Texas Medical Branch , Galveston, TX 77555"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5084-4437","authenticated-orcid":false,"given":"Jiaren","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch , Galveston, TX 77555"},{"name":"Department of Pathology, University of Texas Medical Branch , Galveston, TX 77555"},{"name":"Institute for Human Infections and Immunity, University of Texas Medical Branch , Galveston, TX 77555"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,6,1]]},"reference":[{"key":"2025030417511954700_r1","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1128\/CMR.18.3.446-464.2005","article-title":"Effects of vitamin a supplementation on immune responses and correlation with clinical outcomes","volume":"18","author":"Villamor","year":"2005","journal-title":"Clin. 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