Glycogen synthase kinase 3 controls T cell exhaustion by regulating NFAT activation

Abstract

Abstract Cellular immunity mediated by CD8+ T cells plays an indispensable role in clearance of bacteria and virus infection and cancers. However, persistent antigen stimulation of CD8+ T cells leads to an exhausted or dysfunctional state characterized by loss of effector function and highly expression of inhibitory receptors during chronic virus infection and in tumors. Numerous studies show that glycogen synthase kinase 3 (GSK3) controls the function and development in immune cells, but whether GSK3 exerts a function in CD8+ T cells is not clearly elucidated. Here we demonstrate that mice with deletion of Gsk3α and Gsk3β in activated CD8+ T cells (DKO) resulted in decreased CTL differentiation and their effector function during acute virus infection. In addition, DKO mice failed to control tumors due to increased expression of inhibitory receptors and augmented T cell exhaustion in tumor-infiltrating CD8+ T cells. Strikingly, anti-PD-1 immunotherapy substantially restored tumor rejection in DKO mice. Mechanistically, GSK3 regulates T cell exhaustion by suppressing TCR-induced nuclear import of NFAT, thereby in turn dampening NFAT-mediated exhaustion-related gene expression, including TOX/TOX2 and PD-1. Thus, we uncovered the molecular mechanisms underlying GSK3 regulation of CTL differentiation and T cell exhaustion in anti-tumor immune responses.