Antigenic Experience Dictates Functional Role of Glycogen Synthase Kinase-3 in Human CD4+ T Cell Responses

Abstract Signals induced by the TCR and CD28 costimulatory pathway have been shown to lead to the inactivation of the constitutively active enzyme, glycogen synthase kinase-3 (GSK3), which has been implicated in the regulation of IL-2 and T cell proliferation. However, it is unknown whether GSK3 plays a similar role in naive and memory CD4+ T cell responses. Here we demonstrate a divergence in the dependency on the inactivation of GSK3 in the proliferative responses of human naive and memory CD4+ T cells. We find that although CD28 costimulation increases the frequency of phospho-GSK3 inactivation in TCR-stimulated naive and memory CD4+ T cells, memory cells are less reliant on GSK3 inactivation for their proliferative responses. Rather we find that GSK3β plays a previously unrecognized role in the selective regulation of the IL-10 recall response by human memory CD4+ T cells. Furthermore, GSK3β-inactivated memory CD4+ T cells acquired the capacity to suppress the bystander proliferation of CD4+ T cells in an IL-10-dependent, cell contact-independent manner. Our findings reveal a dichotomy present in the function of GSK3 in distinct human CD4+ T cell populations.