Abrogation of functional selectin-ligand expression reduces migration of pathogenic CD8+ T cells into heart.
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.
Cai
Yi Hong
YH
Vascular Research Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Alvarez
Angeles
A
Alcaide
Pilar
P
Duramad
Paurene
P
Lim
Yaw-Chin
YC
Jarolim
Petr
P
Lowe
John B
JB
Luscinskas
Francis W
FW
Lichtman
Andrew H
AH
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
D019040:E-Selectin; D008024:Ligands; D019007:P-Selectin; C502597:FUT7 protein, human; D005647:Fucosyltransferases