GSK-3β inhibition preserves naive T cell phenotype in bone marrow reconstituted mice

Hematopoietic stem cell transplantation (HSCT) is used in the treatment of hematologic and nonhematologic disorders. PostHSCT immunologic reconstitution is a critical component for successful outcome. Pretransplant conditioning impairs thymic function, leading to delayed T cell regeneration. Thymus-independent T cell expansion is associated with defective generation of naive T cells and memory T cell skewing, resulting in decreased diversity in the T cell repertoire, thus attenuating the immune responses and increasing the risk of opportunistic infections and leukemia relapse. Wingless (Wnt) signaling has been identified as an important regulator of T cell development and function. Activated Wnt signaling inhibited differentiation of mature T cells in transgenic mouse models. The effect of Wnt activation on T cell regeneration following HSCT was not investigated. In this study, we demonstrate that the GSK-3β inhibitor 6-bromoindirubin 3'-oxime (BIO) activates Wnt/β-catenin signaling, elevates the proportion of naive T cells, and delays T cell differentiation during homeostatic T cell expansion in lymphodepleted mice transplanted with human hematopoietic stem cells. In vitro BIO-treatment promoted naive T cell expansion following mitogenic stimulation and improved proliferative responses of T cells to allogeneic stimuli. Treatment with BIO acts to expand the IL7Rα(+) subset of naive T cells, suggesting the potential mechanism driving T cell expansion during IL-7-dependent T cell proliferation. BIO downregulated expression of genes activated during effector cell differentiation and preserved naive T cell gene expression. We propose that administration of GSK-3β inhibitor increases the potency of T cells in recipients of HSCT by expansion of naive T cell subsets with a diverse T cell receptor repertoire.