title: T-bet controls pathogenicity of CTLs in the heart by separable effects on migration and effector activity.
abstract: 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.
authors.affiliation: Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Viviany R
authors.initials: VR
authors.lastname: Taqueti
authors.forename: Nir
authors.initials: N
authors.lastname: Grabie
authors.forename: Richard
authors.initials: R
authors.lastname: Colvin
authors.forename: Hong
authors.initials: H
authors.lastname: Pang
authors.forename: Petr
authors.initials: P
authors.lastname: Jarolim
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D000818:Animals; D016827:CD8 Antigens / Q000032:analysis; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009205:Myocarditis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010641:Phenotype; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D016827:CD8 Antigens; C515188:Cxcr3 protein, mouse; D016207:Cytokines; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor