T-bet-deficient CD8+ T cells showed significantly impaired ability to cause myocarditis, driven by reduced CXCR3-dependent migration and decreased cytotoxicity.
T-bet controls the pathogenicity of CD8+ T cells in immune-mediated heart disease through separable effects on CXCR3-dependent migration and effector activity.
CD8+ CTL contribute to the pathogenesis of myocarditis and cardiac allograft rejection. Using a transgenic model of myocarditis, we examined the role of the transcription factor T-bet in the differentiation of pathogenic cardiac Ag-specific CTL. We demonstrate that T-bet-deficient CTL are significantly impaired in their ability to cause disease, despite intact proliferation and activation phenotypes. In the absence of T-bet, there is markedly reduced expression of the chemokine receptor CXCR3, and CXCR3-gene knockout CTL are significantly less pathogenic than control CTL. Retroviral-mediated CXCR3 expression in T-bet-deficient CD8+ T cells reconstitutes their ability to infiltrate but not to damage the heart, establishing that CD8+ T cell pathogenicity is related to T-bet-dependent CXCR3 expression, reduced cytotoxicity, and enhanced regulation. These findings highlight the potential therapeutic benefit of targeting T-bet-regulated gene expression and CXCR3-dependent migration in immune-mediated heart disease.
Taqueti et al. (Wed,) conducted a other in Myocarditis. T-bet deficiency vs. Control CTLs was evaluated on Pathogenicity of cardiac Ag-specific CTLs. T-bet-deficient CD8+ T cells showed significantly impaired ability to cause myocarditis, driven by reduced CXCR3-dependent migration and decreased cytotoxicity.