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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© 2013 Published by Elsevier Inc.