Unknown

Dataset Information

0

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-7R? 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.

SUBMITTER: Sarraj B 

PROVIDER: S-EPMC4143062 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Sarraj Bara B   Ye Junsheng J   Akl Ahmed Ibrahim AI   Chen Guodong G   Wang Jiao-Jing JJ   Zhang Zheng Z   Abadja Farida F   Abecassis Michael M   Miller Stephen D SD   Kansas Geoffrey S GS   Ansari M Javeed MJ  

Proceedings of the National Academy of Sciences of the United States of America 20140804 33


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, charac  ...[more]

Similar Datasets

| S-EPMC10626464 | biostudies-literature
| S-EPMC4291902 | biostudies-other
| S-EPMC1867022 | biostudies-literature
| S-EPMC3722875 | biostudies-literature
| S-EPMC5333968 | biostudies-literature
2023-07-10 | GSE236626 | GEO
| S-EPMC2998130 | biostudies-literature
| S-EPMC5409881 | biostudies-literature
| S-EPMC3181350 | biostudies-literature
| S-EPMC31181 | biostudies-literature