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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

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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 5

PIM-2–/– T cells mediate GVL effect in MLL-AF9 model.

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PIM-2–/– T cells mediate GVL effect in MLL-AF9 model.
Lethally irradiate...
Lethally irradiated (700 cGy) BALB/c mice underwent transplantation with 5 × 106 TCD-BM per mouse or BM plus 2.5 × 104 T cells per mouse isolated from WT or PIM-2–/– FVB donors and 2 × 104 MLL-AF9-GFP. (A) Percentages of MLL-AF9 cells that were CD11b+GFP+ were analyzed in peripheral blood, and representative dot plots on days 14, 21, 28, and 35 are shown (n = 14 mice per group). (B) Bar graph shows quantified GFP percentages of MLL-AF9 in blood at the indicated time points. (C) Survival of recipient mice was monitored (n = 14 mice per group). Data are pooled from 2 independent experiments and shown as mean ± SEM by 1-way ANOVA and Tukey’s HSD post hoc analysis (B) and log-rank test (C). *P < 0.05, ***P < 0.001, ****P < 0.0001.
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