Investigations into the Myhc 334-352-specific TCR transgenic mice reveal a role for cytotoxic CD4 T cells in the development of cardiac autoimmunity

• Published in: The Journal of immunology (1950) Vol. 212; no. 1_Supplement; pp. 33 - 33_4159
• Main Authors: Sur, Meghna, Rasquinha, Mahima, Mone, Kiruthiga, Lasrado, Ninaad, Massilamany, Chandirasegaran, Sobel, Raymond, Reddy, Jay
• Format: Journal Article
• Language: English
• Published: 01-05-2024
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.212.supp.0033.4159

Myocarditis is a major cause of heart failure in children and young adults that can lead to dilated cardiomyopathy. Lymphocytic myocarditis may result from autoreactive CD4 and CD8 T cells but defining their antigen specificity in disease pathogenesis is challenging. To address this issue, we generated T cell receptor (TCR) transgenic (Tg) C57Bl/6 mice specific to cardiac myosin heavy chain (Myhc)-α 334-352 and found that Myhc-specific TCRs were expressed in both CD4 and CD8 T cells. By backcrossing onto A/J mice for four generations, we noted that Tg T cells from naïve mice respond to Myhc-α 334-352 as evaluated by proliferation assay and carboxyfluorescein succinimidyl ester staining. The T cell responses included significant production of pro-inflammatory cytokines including interferon (IFN)-γ, interleukin-17, granulocyte macrophage-colony stimulating factor, and tumor necrosis factor-α. While the naïve Tg mice had isolated myocardial lesions, immunization with Myhc-α 334-352 led to mild myocarditis, suggesting fully backcrossed mice may show more severe disease. Further studies led us to note that the 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-γ and granzyme B. Taken together, the transgenic system described here may be helpful to distinguish the roles of cytotoxic cardiac antigen-specific CD4 T cells vs. those of CD8 T cells in the pathogenesis of myocarditis.