BCL2 overexpression in donor lymphocytes reduces the risk of graft-versus-host disease

Graft-versus-host disease (GVHD) is a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. BCL2 overexpression has been related to a higher risk of GVHD and glucocorticoid resistance. In this study, we aimed to evaluate the role of BCL2 in GVHD pathophysiology. Remarkably, we observed that the pharmacological inhibition of BCL2 increased the risk of GVHD in murine models. In addition, we used a GVHD model with C57BL/6 donor mice that constitutively overexpress human BCL2 gene in hematopoietic cells (Vav-BCL2). Interestingly, the overexpression of BCL2 in donor lymphocytes was related to a lower risk and severity of GVHD. In vitro, the BCL2 inhibitor venetoclax significantly hampered resting T-cell viability, but it did not affect activated lymphocytes, at least in part because of reduced BCL2 interacting mediator of cell death-BCL2 binding after activation. Moreover, BCL2 overexpressing T cells had compromised functionality. Overexpression of BCL2 had no deleterious effect on graft-versus-leukemia activity. Finally, in vitro studies showed that exposure to steroids enriched the populations of T cells displaying higher BCL2 expression levels. Therefore, our study shows that high expression of BCL2 decreases the risk and severity of GVHD.