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.adhesion | traffic | apoptosis

Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice

“…Exhausted T cells express a variety of coinhibitory receptors, including PD1, TIM3, LAG3, CTLA4, CD160, and BLTA, that modulate the intracellular signaling responsible for this state (24). Although reversal of T-cell exhaustion may be useful in the treatment of chronic infections and cancers, induction of T-cell exhaustion may promote tolerance to autoantigens and alloantigens (24,25). T-cell exhaustion has recently been shown to play a central role in determining clinical outcome in multiple autoimmune diseases (26), and it has been suggested that targeted induction of exhaustion could benefit patients with an aggressive course of disease.…”

IL-10 Induces T Cell Exhaustion During Transplantation of Virus Infected Hearts

“…Further, the role of T cell exhaustion in transplantation or autoimmunity is not defined. Recently, Sarraj et al [36] showed that genetic depletion of selectin ligand for leucocyte migration led to impaired T cell function. They focused on CD4…”

T-cell exhaustion in allograft rejection and tolerance

“…The most direct evidence for T-cell exhaustion in transplantation was provided recently in a model of chronic allograft rejection [36 ▪ ] in which fucosyltransferase-VII–deficient ( Fut7 −/− ) recipients, with impaired selectin-dependent leukocyte recruitment, exhibited long-term graft survival with minimal vasculopathy compared with wild-type 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 PD-1, Tim-3 and KLRG1, low levels of IL-7Rα on CD4 + T cells and reduced polyfunctional CD4 + memory T cells in the allograft.…”

“…In situations in which donor tissue mass is relatively constant, adoptive transfer experiments in a single recipient with a heart transplant, T cells with differential ability to migrate to the allograft behaved very differently – T cells that could not migrate to the allograft exhibited features of exhaustion [36 ▪ ]. These data are consistent with a report that chemokine (C–C motif) ligand 5 (CCL5)-deficient (CCL5 −/− ) recipients with impaired T-cell recruitment were unable to clear LCMV infection and CCL5 −/− CD8 + T cells exhibited features of exhaustion [49].…”