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 Jenny Zhang, Farida Abadja, Michael Messod Abecassis, Stephen D Miller, Geoffrey Scott Kansas, Mohammed Javeed I Ansari*

*Corresponding author for this work

Research output: Contribution to journalArticle

21 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

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Keywords

  • Adhesion
  • Apoptosis
  • Traffic

ASJC Scopus subject areas

  • General

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