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J Clin Invest. 2018 Jul 2;128(7):2787-2801. doi: 10.1172/JCI95407. Epub 2018 May 21.

PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity.

Author information

1
Department of Microbiology and Immunology.
2
Department of Surgery, and.
3
Department of Public Health Science, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
4
University of Arizona Cancer Center, Tucson, Arizona, USA.
5
Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.

Abstract

PIM kinase family members play a crucial role in promoting cell survival and proliferation via phosphorylation of their target substrates. In this study, we investigated the role of the PIM kinases with respect to T cell responses in transplantation and tumor immunity. We found that the PIM-2 isoform negatively regulated T cell responses to alloantigen, in contrast to the PIM-1 and PIM-3 isoforms, which acted as positive regulators. T cells deficient in PIM-2 demonstrated increased T cell differentiation toward Th1 subset, proliferation, and migration to target organs after allogeneic bone marrow transplantation, resulting in dramatically accelerated graft-versus-host disease (GVHD) severity. Restoration of PIM-2 expression markedly attenuated the pathogenicity of PIM-2-deficient T cells to induce GVHD. On the other hand, mice deficient in PIM-2 readily rejected syngeneic tumor, which was primarily dependent on CD8+ T cells. Furthermore, silencing PIM-2 in polyclonal or antigen-specific CD8+ T cells substantially enhanced their antitumor response in adoptive T cell immunotherapy. We conclude that PIM-2 kinase plays a prominent role in suppressing T cell responses, and provide a strong rationale to target PIM-2 for cancer immunotherapy.

KEYWORDS:

Bone marrow transplantation; Cancer immunotherapy; Immunology; Transplantation

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