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

Bara Sarraj, Junsheng Ye, Ahmed Ibrahim Akl, Guodong Chen, Jiao Jing Wang, Zheng Zhang, Farida Abadja, Michael Abecassis, Stephen D. Miller, Geoffrey S. Kansas, M. Javeed Ansari*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Selectin - selectin ligand interactions mediate the initial steps in leukocyte migration, an integral part of immune responses. Fucosyl-transferase- 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.

Original languageEnglish (US)
Pages (from-to)12145-12150
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number33
DOIs
StatePublished - Aug 19 2014

Keywords

  • Adhesion
  • Apoptosis
  • Traffic

ASJC Scopus subject areas

  • General

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