<em>In vivo</em> GSK-3beta Inhibition Promotes T-cell Reconstitution in Bone Marrow Reconstituted Mice — ASN Events
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In vivo GSK-3beta Inhibition Promotes T-cell Reconstitution in Bone Marrow Reconstituted Mice (#405)

Sylvie Shen 1 2 3 , Guy Klamer 1 2 3 , Ning Xu 1 3 , Tracey A O'Brien 1 2 3 , Alla Dolnikov 1 2 3
  1. Cord & Marrow Transplant Facility, CCC&BD, SCH, Randwick, nsw, Australia
  2. Faculty of Medicine, UNSW, Sydney, NSW, Australia
  3. Children’s Cancer Institute Australia for Medical Research, Sydney, NSW, Australia

Stem cell transplantation has become a widely used procedure in the treatment of haematological and non-haematological clinical disorders. Unfortunately, cure is often hampered by relapse of the underlying disease, graft-versus-host disease (GVHD), or severe opportunistic infections. Slow T-cell reconstitution is regarded as primarily responsible for infections, GVHD and relapse, therefore, enhancing immune reconstitution is important. Glycogen synthase kinase-3β (GSK3β) was identified as an important regulator of T cell function acting through the Wingless pathway. Mice transplanted with cord blood CD34+ stem cells demonstrated multilineage reconstitution including myeloid, B and T cell lymphoid compartments. De novo generated human T cells exhibited strong proliferative responses to mitogenic and allogeneic stimulation in vitro but did not demonstrate CTL activity. Late memory T cell skewing was observed in PB and spleen presumably associated with the impaired thymic function. GSK3β inhibition using the small molecule inhibitor BIO promoted T-cell reconstitution. Per cell output of T-cell from CD34+ and CD34+CD38- primitive bone marrow progenitor cells was higher in BIO-treated mice while CD19+ B-cell output was reduced, suggesting T-cell developmental skewing in expense of B-cell development. In vitro analysis of CD34+ progenitor cells co-cultured with bone marrow stroma MS5 cells has demonstrated inhibited B-cell development following BIO treatment. GSK3β inhibition increased naïve:effector T-cell ratio in reconstituted mice and increased the percentage and number of naïve T-cells in activated T-cells in vitro. GSK3β inhibition preserved naïve T-cell gene expression profile and suppressed the expression of genes activated during effector T-cell differentiation. BIO activated β-catenin signalling and up-regulated IL7Rα, the naïve T cell marker. We hypothesise that GSK3β inhibition acts to preserve a subset of naïve T cells, and may thus increase T-cell diversity and promote T-cell responses in the recipients of CB transplant, particularly in adult patients with impaired thymic function.