The Presence of Activated T Cell Subsets prior to Transplantation Is Associated with Increased Rejection Risk in Pancreas Transplant Recipients

Abstract

Pancreas and islet transplantation (PTx) are currently the only curative treatment options for type 1 diabetes. CD4⁺ and CD8⁺ T cells play a pivotal role in graft function, rejection, and survival. However, characterization of immune cell status from patients with and without rejection of the pancreas graft is lacking. We performed multiparameter immune phenotyping of T cells from PTx patients prior to and 1 y post-PTx in nonrejectors and histologically confirmed rejectors. Our results suggest that rejection is associated with presence of elevated levels of activated CD4⁺ and CD8⁺ T cells with a gut-homing phenotype both prior to and 1 y post-PTx. The CD4⁺ and CD8⁺ T cells were highly differentiated, with elevated levels of type 1 inflammatory markers (T-bet and INF-γ) and cytotoxic components (granzyme B and perforin). Furthermore, we observed increased levels of activated FOXP3⁺ regulatory T cells in rejectors, which was associated with a hyporesponsive phenotype of activated effector T cells. Finally, activated T and B cell status was correlated in PTx patients, indicating a potential interplay between these cell types. In vitro treatment of healthy CD4⁺ and CD8⁺ T cells with tacrolimus abrogated the proliferation and cytokine (INF-γ, IL-2, and TNF-α) secretion associated with the type 1 inflammatory phenotype observed in pre- and post-PTx rejectors. Together, our results suggest the presence of activated CD4⁺ and CD8⁺ T cells prior to PTx confer increased risk for rejection. These findings may be used to identify patients that may benefit from more intense immunosuppressive treatment that should be monitored more closely after transplantation.