title: Impaired selectin-dependent leukocyte recruitment induces T-cell exhaustion and prevents chronic allograft vasculopathy and rejection.
abstract: Selectin-selectin ligand interactions mediate the initial steps in leukocyte migration, an integral part of immune responses. Fucosyltransferase-VII (FucT-VII), encoded by Fut7, is essential for biosynthesis of selectin ligands. In an established model of cardiac allograft vasculopathy and chronic rejection, Fut7(-/-) recipients exhibited long-term graft survival with minimal vasculopathy compared with WT controls. Graft survival was associated with CD4 T-cell exhaustion in the periphery, characterized by impaired effector cytokine production, defective proliferation, increased expression of inhibitory receptors programmed death-1 (PD-1) and T cell Ig- and mucin-domain-containing molecule-3 (Tim-3), low levels of IL-7Rα on CD4 T cells, and reduced migration of polyfunctional CD4 memory T cells to the allograft. Blocking PD-1 triggered rejection only in Fut7(-/-) recipients, whereas depleting regulatory T cells had no effect in either Fut7(-/-) or WT recipients. Adoptive transfer experiments confirmed that this CD4 T cell-exhausted phenotype is seen primarily in Fut7(-/-) CD4 T cells. These data suggest that impaired leukocyte recruitment is a novel mechanism leading to CD4 T-cell exhaustion. Our experimental system serves as an excellent model to study CD4 T-cell exhaustion as a dominant mechanism of transplant tolerance. Further, targeting FucT-VII may serve as a promising strategy to prevent chronic allograft rejection and promote tolerance.
authors.affiliation: Division of Nephrology, Department of Medicine,Division of Organ Transplantation, Department of Surgery, and.
authors.forename: Bara
authors.initials: B
authors.lastname: Sarraj
authors.affiliation: Division of Organ Transplantation, Department of Surgery, andDepartment of Kidney Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Junsheng
authors.initials: J
authors.lastname: Ye
authors.affiliation: Division of Nephrology, Department of Medicine.
authors.forename: Ahmed Ibrahim
authors.initials: AI
authors.lastname: Akl
authors.affiliation: Division of Organ Transplantation, Department of Surgery, and.
authors.forename: Guodong
authors.initials: G
authors.lastname: Chen
authors.affiliation: Division of Organ Transplantation, Department of Surgery, and.
authors.forename: Jiao-Jing
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Division of Organ Transplantation, Department of Surgery, and.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Division of Organ Transplantation, Department of Surgery, and.
authors.forename: Farida
authors.initials: F
authors.lastname: Abadja
authors.affiliation: Division of Organ Transplantation, Department of Surgery, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Abecassis
authors.affiliation: Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
authors.affiliation: Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Kansas
authors.affiliation: Division of Nephrology, Department of Medicine,Division of Organ Transplantation, Department of Surgery, and jansari@northwestern.edu.
authors.forename: M Javeed
authors.initials: MJ
authors.lastname: Ansari
mesh_terms: D019264:Adoptive Transfer; D064591:Allografts; D001808:Blood Vessels / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement; D005434:Flow Cytometry; D005647:Fucosyltransferases / Q000235:genetics; D006084:Graft Rejection; D006801:Humans; D007962:Leukocytes / Q000166:cytology*; D019087:Selectins / Q000502:physiology*
chemical_list: D019087:Selectins; C502597:FUT7 protein, human; D005647:Fucosyltransferases
keywords: adhesion; apoptosis; traffic
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