Inhibition of T cell function in vitro and in vivo using small molecule antagonists of PIM kinases (35.33)

Abstract

Abstract The PIM family consists of three highly conserved serine/threonine kinases whose activity is regulated at the level of expression. PIM kinase expression has been shown to be stimulated by a variety of cytokines, hormones, and mitogens and it functions in the regulation of cellular proliferation, differentiation, apoptosis and tumorigenesis. The role of PIM-induced oncogenic transformation has been extensively studied in hematopoietically derived tumors; however the function of PIM in normal immune cells has yet to be fully defined. We sought to elucidate the role of PIM in activation of primary murine T cells by utilizing a highly selective, small molecule PIM inhibitor. We found that inhibition of PIM activity resulted in decreased anti-CD3 and antigen-induced CD4+ T cell proliferation. These effects were observed under Th0, Th1, Th2 and Th17 polarizing conditions, and were not due to increased cell death, but appear to be mediated by a G0/G1 cell cycle arrest. Inhibition of PIM during polarization prevented the production of Th1, Th2, and Th17 effector cytokines suggesting that PIM expression is required for naïve T cell differentiation. Consistent with the in vitro data, mice treated with the PIM inhibitor prior to immunization had a significant reduction in ex vivo recall responses. These results support a key role for PIM in the activation and differentiation of murine CD4+ T cells.