IFN-γ-producing Th1-like regulatory T cells may limit acute cellular renal allograft rejection: Paradoxical post-transplantation effects of IFN-γ

Purpose: IFN-gamma is a protypical proinflammatory cytokine that plays a central role in inflammation and acute graft rejection. Accumulating evidence indicates that IFN-gamma can exert previously unexpected immunoregulatory activities. However, little is known about the role of IFN-gamma secreted by Th1-like regulatory T cells in human kidney transplantation. Methods: To determine the function of IFN-gamma in acute T cell-mediated renal allograft rejection (ACR), we examined serum cytokine expression profiles in ACR patients by human cytokine multiplex immunoassay and analyzed the cellular origins of IFN-gamma in peripheral blood and renal allograft biopsies from ACR cases and controls by flow cytometry and immunohistochemistry, respectively. Results: The results showed significant reduction in serum concentrations of Th1-inducing cytokines IL-12p70 and IFN-gamma as well as Th2-related cytokine IL-4 in ACR patients compared with stable controls. However, levels of several Th1-, Th2- and Th17-related cytokines, such as IL-2, TNF-alpha, TNF-beta, IL-12 (p40), IL-10, 1L-15, IL-17, IL-21, and IL-23, as well as the frequencies of Th1 and Th17 cell, did not differ between ACR cases and stable controls. Moreover, we found the levels of IFN-gamma were correlated with those of the anti-inflammatory factor, IL-1 receptor antagonist (IL-1Ra) in ACR. Notably, the Th1-like Treg cell-to-Foxp3(-) Th1 cell ratio was significantly lower in ACR patients compared with that in stable controls. In graft biopsies from ACR patients, Treg cells and Th1-like Treg cells were less abundant than those without ACR. Conclusions: Our study indicates that IFN-gamma secreted from Th1-like Treg cells negatively modulates ACR. (C) 2016 Elsevier GmbH. All rights reserved.