{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T07:18:23Z","timestamp":1791875903826,"version":"4.3.4"},"reference-count":69,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T00:00:00Z","timestamp":1706227200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R21AI142281-02"],"award-info":[{"award-number":["5R21AI142281-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Myocarditis is one of the major causes of heart failure in children and young adults and can lead to dilated cardiomyopathy. Lymphocytic myocarditis could result from autoreactive CD4+ and CD8+ T cells, but defining antigen specificity in disease pathogenesis is challenging. To address this issue, we generated T cell receptor (TCR) transgenic (Tg) C57BL\/6J mice specific to cardiac myosin heavy chain (Myhc)-\u03b1 334\u2013352 and found that Myhc-\u03b1-specific TCRs were expressed in both CD4+ and CD8+ T cells. To investigate if the phenotype is more pronounced in a myocarditis-susceptible genetic background, we backcrossed with A\/J mice. At the fourth generation of backcrossing, we observed that Tg T cells from na\u00efve mice responded to Myhc-\u03b1 334\u2013352, as evaluated by proliferation assay and carboxyfluorescein succinimidyl ester staining. The T cell responses included significant production of mainly pro-inflammatory cytokines, namely interferon (IFN)-\u03b3, interleukin-17, and granulocyte macrophage-colony stimulating factor. While the na\u00efve Tg mice had isolated myocardial lesions, immunization with Myhc-\u03b1 334\u2013352 led to mild myocarditis, suggesting that further backcrossing to increase the percentage of A\/J genome close to 99.99% might show a more severe disease phenotype. Further investigations led us to note that CD4+ T cells displayed the phenotype of cytotoxic T cells (CTLs) akin to those of conventional CD8+ CTLs, as determined by the expression of CD107a, IFN-\u03b3, granzyme B natural killer cell receptor (NKG)2A, NKG2D, cytotoxic and regulatory T cell molecules, and eomesodermin. Taken together, the transgenic system described in this report may be a helpful tool to distinguish the roles of cytotoxic cardiac antigen-specific CD4+ T cells vs. those of CD8+ T cells in the pathogenesis of myocarditis.<\/jats:p>","DOI":"10.3390\/cells13030234","type":"journal-article","created":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T04:05:46Z","timestamp":1706241946000},"page":"234","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Investigation into Cardiac Myhc-\u03b1 334\u2013352-Specific TCR Transgenic Mice Reveals a Role for Cytotoxic CD4 T Cells in the Development of Cardiac Autoimmunity"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0878-4930","authenticated-orcid":false,"given":"Meghna","family":"Sur","sequence":"first","affiliation":[{"name":"School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68588, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0923-4869","authenticated-orcid":false,"given":"Mahima T.","family":"Rasquinha","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68588, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0379-4152","authenticated-orcid":false,"given":"Kiruthiga","family":"Mone","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68588, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandirasegaran","family":"Massilamany","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68588, USA"},{"name":"CRISPR Therapeutics, Boston, MA 02127, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6762-2654","authenticated-orcid":false,"given":"Ninaad","family":"Lasrado","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68588, USA"},{"name":"Center for Virology and Vaccine Research, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Channabasavaiah","family":"Gurumurthy","sequence":"additional","affiliation":[{"name":"Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0477-9002","authenticated-orcid":false,"given":"Raymond A.","family":"Sobel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4082-9254","authenticated-orcid":false,"given":"Jay","family":"Reddy","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68588, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1007\/s12013-015-0550-7","article-title":"The Inflammatory Heart Diseases: Causes, Symptoms, and Treatments","volume":"72","author":"Lu","year":"2015","journal-title":"Cell Biochem. 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