PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity
Anusara Daenthanasanmak, … , Andrew S. Kraft, Xue-Zhong Yu
Anusara Daenthanasanmak, … , Andrew S. Kraft, Xue-Zhong Yu
Published May 21, 2018
Citation Information: J Clin Invest. 2018;128(7):2787-2801. https://doi.org/10.1172/JCI95407.
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Research Article Immunology Transplantation

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

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.

Authors

Anusara Daenthanasanmak, Yongxia Wu, Supinya Iamsawat, Hung D. Nguyen, David Bastian, MengMeng Zhang, M. Hanief Sofi, Shilpak Chatterjee, Elizabeth G. Hill, Shikhar Mehrotra, Andrew S. Kraft, Xue-Zhong Yu

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Figure 1

Distinct roles of PIM kinases in T cell alloresponses after BMT.

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Distinct roles of PIM kinases in T cell alloresponses after BMT. WT B6 m...
WT B6 mice were lethally irradiated at 950–1,000 cGy. These recipients then underwent transplantation with WT TCD-BM alone or plus 2 × 106 total T cells isolated from WT, PIM-1–/–, PIM-2–/–, PIM-1/2–/–, PIM-1/3–/–, PIM-2/3–/– double-KO, or PIM-1/2/3 triple-KO (TKO) on an FVB background. Recipient mice were monitored for survival (A and C) and body weight changes (B and D) over time. The data shown in A and B were pooled from 2 replicate experiments (n = 10–12 per group), while the data in C and D were obtained from 1 experiment (n = 5–6 per group). Significance was determined by log-rank test. *P < 0.05, **P < 0.01, ***P < 0.001.