Transcriptional analysis of beta-catenin overexpressing T cells

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most widely applied forms of adaptive immunotherapy. Both the detrimental graft-versus-host disease (GVHD) and the beneficial graft-versus-leukemia (GVL) effects occurring after allo-HSCT are largely mediated by alloantigen-reactive donor T cells in the graft. Separating GVHD from GVL effects is a formidable challenge, and a greater understanding of donor T cell biology is required to accomplish the uncoupling of GVHD from GVL. Here, we tested a novel mouse model of transgenic over-expression of human ß-catenin (Cat-Tg) in an allo-HSCT model. Our data show that T cells from Cat-Tg mice did not cause GVHD. Surprisingly, Cat-Tg T cells maintained the GVL effect. Donor T cells from Cat-Tg mice exhibited significantly lower inflammatory cytokine production and reduced donor T cell proliferation, while upregulating cytotoxic mediators that resulted in enhanced cytotoxicity. RNA sequencing data revealed changes in the expression of 1169 genes for CD4, and 1006 genes for CD8+T cells involved in essential aspects of immune response and GVHD pathophysiology. Transgenic over-expression of human ß-catenin primarily affects CD8+ T cell phenotype. Altogether, our data suggest that ß-catenin is a druggable target for developing therapeutic strategies to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment Overall design: We analyzed FACS purified CD4 and CD8 T cells of 3 different human beta catenin overexpressing(Cat-Tg) and WT mouse, along with CD4 and CD8 T Cells of Cat-Tg and WT mouse that were initially transplanted into lethally irradiated recipent Balb/c mouse and were FACS purified after day 7 post transplant from the spleen of recipients.