title: Abrogation of functional selectin-ligand expression reduces migration of pathogenic CD8+ T cells into heart.
abstract: CD8+ T cells are involved in autoimmune and infectious myocarditis and cardiac allograft rejection. The role of selectins in cardiac recruitment of CD8+ T cells is not understood. In this study, the contribution of T cell selectin ligands to effector CD8+ T cell recruitment into the heart was examined using a model of myocarditis, which depends on transfer of OVA peptide-specific CD8+ T cells (OT-I) into mice (CMy-mOva) that express OVA in the heart. alpha-(1,3)-Fucosyltransferase (FucT)-VII-deficient OT-I cells displayed over a 95% reduction in their ability to interact with P-selectin under flow conditions in vitro, compared with wild-type OT-I cells. Interaction of FucT-VII-deficient OT-I cells with E-selectin was reduced approximately 50%. FucT-VII-deficient OT-I cells were also less efficiently recruited into a dermal site of Ag and adjuvant injection. Significantly, FucT-VII-deficient OT-I cells were also impaired in their ability to migrate into CMy-mOva hearts, compared with wild-type OT-I cells. Transfer of FucT-VII-deficient T cells caused less severe early myocarditis and myocyte damage than transfer of wild-type T cells. Combined FucT-IV/VII-deficient OT-I cells displayed a more profound reduction in E-selectin interactions in vitro compared with FucT-VII-deficient T cells, and the FucT-IV/VII-deficient T cells also showed less early recruitment and pathogenicity in the CMy-mOva myocarditis model. These results identify a prominent role for selectin ligands in contributing to effector CD8+ T cell recruitment into the myocardium and indicate that selectin-dependent T cell recruitment is relevant to other tissues besides the skin.
authors.affiliation: Vascular Research Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yi Hong
authors.initials: YH
authors.lastname: Cai
authors.forename: Angeles
authors.initials: A
authors.lastname: Alvarez
authors.forename: Pilar
authors.initials: P
authors.lastname: Alcaide
authors.forename: Paurene
authors.initials: P
authors.lastname: Duramad
authors.forename: Yaw-Chin
authors.initials: YC
authors.lastname: Lim
authors.forename: Petr
authors.initials: P
authors.lastname: Jarolim
authors.forename: John B
authors.initials: JB
authors.lastname: Lowe
authors.forename: Francis W
authors.initials: FW
authors.lastname: Luscinskas
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D019040:E-Selectin / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D005647:Fucosyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009205:Myocarditis / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control; D019007:P-Selectin / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D012867:Skin / Q000166:cytology / Q000276:immunology
chemical_list: D019040:E-Selectin; D008024:Ligands; D019007:P-Selectin; C502597:FUT7 protein, human; D005647:Fucosyltransferases