Journal
JOURNAL OF IMMUNOLOGY
Volume 177, Issue 9, Pages 5890-5901Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.177.9.5890
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Funding
- NCI NIH HHS [CA 48126, CA 69212] Funding Source: Medline
- NHLBI NIH HHS [HL 072056] Funding Source: Medline
- NIAID NIH HHS [AI 059610, AI 56296] Funding Source: Medline
- NIDDK NIH HHS [DK 074449] Funding Source: Medline
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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 CXCR3gene 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.
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