| First Author | Sur M | Year | 2024 |
| Journal | Cells | Volume | 13 |
| Issue | 3 | PubMed ID | 38334626 |
| Mgi Jnum | J:358518 | Mgi Id | MGI:7594438 |
| Doi | 10.3390/cells13030234 | Citation | Sur M, et al. (2024) Investigation into Cardiac Myhc-alpha 334-352-Specific TCR Transgenic Mice Reveals a Role for Cytotoxic CD4 T Cells in the Development of Cardiac Autoimmunity. Cells 13(3) |
| abstractText | 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)-alpha 334-352 and found that Myhc-alpha-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 naive mice responded to Myhc-alpha 334-352, 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)-gamma, interleukin-17, and granulocyte macrophage-colony stimulating factor. While the naive Tg mice had isolated myocardial lesions, immunization with Myhc-alpha 334-352 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-gamma, 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. |
