Inhibition of Pim2-prolonged skin allograft survival through the apoptosis regulation pathway

Abstract

Recently, apoptosis has been considered to be an important regulator for allograft survival. The serine/threonine kinase Pim2 has been implicated in many apoptotic pathways. In a previous study, we found that pim2 was highly expressed in CD4⁺ T cells in an allograft model. Here, we further investigated the effects of Pim2 on allograft survival and the underlying mechanisms associated with apoptosis. The results showed that pim2 was overexpressed in grafts and spleens, particularly in spleen CD4⁺ T cells when acute allorejection occurred, and correlated positively with the extent of rejection. In T cells from the spleens of naive BALB/c mice treated with 5 µM 4a (a specific inhibitor of Pim2) for 24 h, the apoptosis rate increased and the phosphorylation of BAD was decreased. Furthermore, adoptive transfer of CD4⁺ T cells treated with 4a in vitro to allografted severe combined immunodeficiency (SCID) mice effectively prolonged allograft survival from 19.5±1.7 days to 31±2.3 days. Moreover, the results demonstrated that the CD4⁺CD25⁻ effector T-cell subset was the predominate expresser of the pim2 gene as compared with the CD4⁺CD25⁺ regulatory T (Treg) cell subset. Alloantigen-induced CD4⁺CD25⁺ T cells displayed less Foxp3 expression and a low suppression of apoptosis compared with effector CD4⁺CD25⁻ T cells treated with 4a. Collectively, these data revealed that Pim2 facilitated allograft rejection primarily by modulating the apoptosis of effector T cells and the function of Treg cells. These data suggested that Pim2 may be an important target for in vivo anti-rejection therapies and for the ex vivo expansion of CD4⁺CD25⁺ T cells.