Impaired selectin-dependent leukocyte recruitment induces T-cell exhaustion and prevents chronic allograft vasculopathy and rejection

Proc Natl Acad Sci U S A. 2014 Aug 19;111(33):12145-50. doi: 10.1073/pnas.1303676111. Epub 2014 Aug 4.


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.

Keywords: adhesion; apoptosis; traffic.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Allografts*
  • Blood Vessels / pathology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Movement
  • Flow Cytometry
  • Fucosyltransferases / genetics
  • Graft Rejection*
  • Humans
  • Leukocytes / cytology*
  • Selectins / physiology*


  • Selectins
  • FUT7 protein, human
  • Fucosyltransferases