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T-bet Controls Pathogenicity of CTLs in the Heart by Separable Effects on Migration and Effector Activity¹

Viviany R. Taqueti^*,, Nir Grabie^*, Richard Colvin, Hong Pang^*, Petr Jarolim, Andrew D. Luster, Laurie H. Glimcher^¶ and Andrew H. Lichtman^2,*

^* Vascular Research Division, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; Division of Health Sciences and Technology, Massachusetts Institute of Technology, Harvard Medical School, Boston, MA 02115; Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129; Laboratory Medicine Division, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and ^¶ Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, MA 02115

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the following National Institutes of Health Grants AI059610 and HL072056 (to A.H.L.); CA48126 and AI56296 (to L.H.G.); and DK074449 and CA69212 (to A.D.L. and R.C.). Additional support came from The Roche Organ Transplantation Research Foundation (to A.D.L.), Howard Hughes Medical Institute Research Training Fellowship, American Medical Association Seed Grant, and American Academy of Allergy, Asthma, and Immunology (to V.R.T.).

² Address correspondence and reprint requests to Dr. Andrew H. Lichtman, Department of Pathology, Brigham and Women’s Hospital, NRB-7, Room 752N, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail address: alichtman{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: EGFP, enhanced GFP; TnI, troponin I; PD-L1, programmed death-ligand 1; TIAP, thymus inhibitor of apoptosis; Mig, monokine induced by IFN-; I-TAC, IFN-inducible T cells chemoattractant; IP-10, IFN-inducible protein 10; Treg, regulatory T cell.

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