title: GSK-3β inhibition preserves naive T cell phenotype in bone marrow reconstituted mice.
abstract: 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.
authors.affiliation: Sydney Cord and Marrow Transplant Facility, Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, Sydney, Australia; School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Shen
authors.forename: Guy
authors.initials: G
authors.lastname: Klamer
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.forename: Tracey A
authors.initials: TA
authors.lastname: O'Brien
authors.forename: Alla
authors.initials: A
authors.lastname: Dolnikov
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D010091:Oximes / Q000494:pharmacology*; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D014183:Transplantation, Heterologous
chemical_list: C483321:6-bromoindirubin-3'-oxime; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3