title: PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis.
abstract: PD-1, a member of the CD28 family of immune regulatory molecules, is expressed on activated T cells, interacts with its ligands, PD-L1/B7-H1 and PD-L2/B7-DC, on other cells, and delivers inhibitory signals to the T cell. We studied the role of this pathway in modulating autoreactive T cell responses in two models of myocarditis. In a CD8(+) T cell-mediated adoptive transfer model, we found that compared with Pd1(+/+) CD8(+) T cells, Pd1(-/-) CD8(+) T cells cause enhanced disease, with increased inflammatory infiltrate, particularly rich in neutrophils. Additionally, we show enhanced proliferation in vivo and enhanced cytotoxic activity of PD-1-deficient T lymphocytes against myocardial endothelial cells in vitro. In experimental autoimmune myocarditis, a disease model dependent on CD4(+) T cells, we show that mice lacking PD-1 develop enhanced disease compared with wild-type mice. PD-1-deficient mice displayed increased inflammation, enhanced serum markers of myocardial damage, and an increased infiltration of inflammatory cells, including CD8(+) T cells. Together, these studies show that PD-1 plays an important role in limiting T cell responses in the heart.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Margarite L
authors.initials: ML
authors.lastname: Tarrio
authors.forename: Nir
authors.initials: N
authors.lastname: Grabie
authors.forename: De-xiu
authors.initials: DX
authors.lastname: Bu
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D032342:Muscle Cells / Q000276:immunology* / Q000473:pathology*; D009205:Myocarditis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D061026:Programmed Cell Death 1 Receptor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology
chemical_list: C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor