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

Graft-versus-host disease (GvHD) is the leading cause of morbi-mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). BCL2-overexpression has been related to a higher risk of GvHD and glucocorticoid (GC) resistance. We aimed to evaluate the role of BCL2 in GvHD pathophysiology. Remarkably, we observed that the pharmacological inhibition of BCL2 increases the risk of GvHD in murine models. In addition, we carried out a GvHD model using as donors C57BL/6 mice that constitutively overexpress the 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 hampers resting T-cells viability while it does not affect activated lymphocytes, at least in part due to reduced BIM/BCL2 binding after activation. Moreover, BCL2-overexpressing T-cells have a compromised functionality. Overexpression of BCL2 had no deleterious effect on GvL. Finally, in vitro studies showed that exposure to steroids enriches 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.