Impaired selectin-dependent leukocyte trafficking induces T cell exhaustion and prevents chronic allograft vasculopathy and rejection (P2140)

Abstract

Abstract Selectin-selectin ligand interactions mediate the initial steps in leukocyte emigration, an integral part of immune response. Fucosyltransferase-VII (FucT-VII) enzyme, encoded by Fut7 gene, is essential for post-translational modification and function of selectin ligands. In an established model of cardiac allograft vasculopathy and chronic rejection, Fut7-/- recipients, with impaired selectin-dependent leukocyte trafficking, enjoyed long-term graft survival with minimal vasculopathy. This was associated with T cell exhaustion in the periphery characterized by impaired effector cytokine production, proliferative defect, increased expression of inhibitory receptors PD-1 and Tim-3 and low levels of IL-7Ra on CD4 T cells and reduced trafficking of polyfunctional CD4 memory T cells to the allograft. Blocking PD-1, triggered rejection only in Fut7-/- recipients, whereas depleting regulatory T cells triggered rejection in WT recipients. Adoptive transfer experiments confirmed that the exhausted phenotype is seen primarily in CD4 T cells with impaired trafficking ability. In summary, these data suggest that impaired leukocyte trafficking is a novel mechanism of CD4 T cell exhaustion and 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.