title: CD43 Functions as an E-Selectin Ligand for Th17 Cells In Vitro and Is Required for Rolling on the Vascular Endothelium and Th17 Cell Recruitment during Inflammation In Vivo.
abstract: Endothelial E- and P-selectins mediate lymphocyte trafficking in inflammatory processes by interacting with lymphocyte selectin ligands. These are differentially expressed among different T cell subsets and function alone or in cooperation to mediate T cell adhesion. In this study, we characterize the expression and functionality of E-selectin ligands in Th type 17 lymphocytes (Th17 cells) and report that CD43 functions as a Th17 cell E-selectin ligand in vitro that mediates Th17 cell rolling on the vascular endothelium and recruitment in vivo. We demonstrate Th17 cells express CD44, P-selectin glycoprotein ligand (PSGL)-1, and CD43. Few PSGL-1(-/-)CD43(-/-) Th17 cells accumulated on E-selectin under shear flow conditions compared with wild-type cells. CD43(-/-) Th17 cell accumulation on E-selectin was impaired as compared with wild-type and PSGL-1(-/-), and similar to that observed for PSGL-1(-/-)CD43(-/-) Th17 cells, indicating that CD43 alone is a dominant ligand for E-selectin. Notably, this finding is Th17 cell subset specific because CD43 requires cooperation with PSGL-1 in Th1 cells for binding to E-selectin. In vivo, Th17 cell recruitment into the air pouch was reduced in CD43(-/-) mice in response to CCL20 or TNF-α, and intravital microscopy studies demonstrated that CD43(-/-) Th17 cells had impaired rolling on TNF-α-treated microvessels. Furthermore, CD43(-/-) mice were protected from experimental autoimmune encephalomyelitis and had impaired recruitment of Th17 cells in the spinal cord. Our findings demonstrate that CD43 is a major E-selectin ligand in Th17 cells that functions independent of PSGL-1, and they suggest that CD43 may hold promise as a therapeutic target to modulate Th17 cell recruitment.
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111.|Sackler School of Biomedical Sciences Immunology program, Tufts University School of Medicine, Boston, MA 02111.
authors.forename: Francisco
authors.initials: F
authors.lastname: Velázquez
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111.
authors.forename: Anna
authors.initials: A
authors.lastname: Grodecki-Pena
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111.
authors.forename: Andrew
authors.initials: A
authors.lastname: Knapp
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111.
authors.forename: Ane M
authors.initials: AM
authors.lastname: Salvador
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111.
authors.forename: Tania
authors.initials: T
authors.lastname: Nevers
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115.
authors.forename: Kevin
authors.initials: K
authors.lastname: Croce
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111.|Sackler School of Biomedical Sciences Immunology program, Tufts University School of Medicine, Boston, MA 02111.|800 Washington St, Box #80, Boston, MA 02111.
authors.forename: Pilar
authors.initials: P
authors.lastname: Alcaide
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D019040:E-Selectin / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology; D005434:Flow Cytometry; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology*; D036904:Leukocyte Rolling / Q000276:immunology*; D051917:Leukosialin / Q000276:immunology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D019040:E-Selectin; D051917:Leukosialin; D008024:Ligands