Impaired Selectin-Dependent Leukocyte Trafficking Induces T-Cell Exhaustion and Prevents Chronic Allograft Vasculopathy and Rejection
Transplant Surgery, Northwestern University Feinberg School of Medicine, Chicago
Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago
Medicine-Nephrology, Northwestern University Feinberg School of Medicine, Chicago
Meeting: 2013 American Transplant Congress
Abstract number: D1766
Selectin-selectin ligand interactions mediate the initial steps in leukocyte emigration, an integral part of immune response. Fucosyltransferase-VII (FucT-VII) enzyme, encoded by Fut7 gene, is essential for post-translational modification and function of selectin ligands.
In an established, single MHC-II mismatched (bm12 into C57BL/6), model of cardiac allograft vasculopathy and chronic rejection, Fut7-/- recipients, with impaired selectin-dependent leukocyte trafficking, enjoyed long-term graft survival (MST: Fut7-/- > 100d vs. WT 53d, p < 0.04) with minimal vasculopathy. 14d post-tx we observed reduced trafficking of APC to the graft and impaired priming of alloreactive T cells and memory generation in the periphery. This was associated with CD4 T cell exhaustion in the periphery characterized by impaired effector cytokine production, proliferative defect (Ki67 and CFSE), increased expression of inhibitory receptors PD-1 and Tim-3 and low levels of IL-7RΑ on CD4 T cells and reduced trafficking of polyfunctional CD4 memory T cells (producing both IFNΓ and IL17A) to the allograft (Fut7-/- 4.05 ± 0.8 x 103 vs. WT 8.5 ± 1.4 x 103, p < 0.05). FoxP3+ CD4 Tregs were not increased in Fut7-/- recipients. Blocking PD-1, triggered rejection only in Fut7-/- recipients (MST: Fut7-/- 22d vs. WT > 40d, p < 0.03), whereas depleting regulatory T cells triggered rejection in WT recipients. We adoptively transferred CD45.2+ FucT-VII deficient and GFP+ WT leukocytes into congenic CD45.1+ WT recipients that were later transplanted with a bm12 heart and observed that a significantly higher proportion of FucT-VII deficient T cells compared to WT T cells expressed PD-1 (39.6 ± 3.6% vs. 4.0 ± 0.89%, p < 0.0001). This confirmed that the exhausted phenotype is seen primarily in CD4 T cells with impaired trafficking ability.
In summary, these data suggest that impaired leukocyte trafficking is a novel mechanism of CD4 T cell exhaustion and 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.
To cite this abstract in AMA style:
Sarraj B, Ye J, Zheng Z, Miller S, Kansas G, Ansari M. Impaired Selectin-Dependent Leukocyte Trafficking Induces T-Cell Exhaustion and Prevents Chronic Allograft Vasculopathy and Rejection [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/impaired-selectin-dependent-leukocyte-trafficking-induces-t-cell-exhaustion-and-prevents-chronic-allograft-vasculopathy-and-rejection/. Accessed December 13, 2024.« Back to 2013 American Transplant Congress