GSK-3β inhibition promotes T cell reconstitution and preserves naïve T cell phenotype in mice transplanted with human haematopoietic stem cells

      Stem cell transplantation (SCT) has become a widely used procedure in the treatment of haematological and non-haematological clinical disorders. Immunologic reconstitution following stem cell transplantation is a critical component for successful outcome. Chemotherapy and pre-conditioning impair thymic function leading to delayed T cell regeneration. The lack of T cells with a broad T-cell receptor repertoire leads to an increased risk for opportunistic infections and leukaemia relapse. Therefore, enhancing immune reconstitution is important. The Wingless pathway (Wnt) was identified as an important regulator of T cell function. In normally functioning thymus thymic epithelial cells provide Wnt signals to developing thymocytes. Chemotherapy and pre-conditioning lead to Wnt depletion due to impaired thymic function. Therefore, providing right dosage of Wnt to the thymocytes following pre-conditioning may provide specific therapeutic option for SCT patients. Here we show that conditional Wnt activation using small molecule inhibitor of Glycogen Synthase Kinase 3β (GSK-3β), 6-bromoindirubin 3′-oxime (BIO), promotes human T cell reconstitution in immuno-compromised mice transplanted with cord blood CD34+ stem cells. BIO treatment did not modulate the proportion of early lymphoid CD34+CD7+ progenitor cells in the bone marrow and thymus but promoted T cell expansion in periphery and increased naïve T (Tn) cell pool preventing effector differentiation during homeostatic T cell proliferation. GSK-3β inhibition in mature human T cells preserved Tn cell gene expression and suppressed the genes activated during effector T cell differentiation. BIO promoted Tn cell divisions induced by IL7 suggesting that GSK-3β inhibition elicits Tn cell expansion promoting crosstalk between Wnt and IL7/IL7Rs signalling. We propose that GSK-3β inhibition can potentially promote T-cell responses in the recipients of stem cell transplant, particularly in adult patients with impaired thymic function.
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