T-bet controls pathogenicity of CTLs in the heart by separable effects on 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
Viviany R
VR
Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Grabie
Nir
N
Colvin
Richard
R
Pang
Hong
H
Jarolim
Petr
P
Luster
Andrew D
AD
Glimcher
Laurie H
LH
Lichtman
Andrew H
AH
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
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