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

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 8

PIM-2 kinase regulates T cell alloresponses through IL-9/IL-9R signaling.

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PIM-2 kinase regulates T cell alloresponses through IL-9/IL-9R signaling...
(A and B) Purified WT or PIM-2–/– T cells were stimulated for 3 days with anti-CD3 and anti-CD28 (5 μg/ml each). The heatmap represents relative expression of RNA level; each graph represents maximum to minimum value of upregulation (A) or downregulation (B). (C) WT or PIM-2–/– CD4+ T cells were stimulated with anti-CD3 and anti-CD28 (2 μg/ml each) and polarized under Th9 polarizing conditions (10 ng/ml IL-4 and 2 ng/ml TGF-β). The representative histogram plot shows mean fluorescence intensity (MFI) of IL-9, and quantified MFI is shown in the bar graph (n = 3). (D and E) Purified T cells of WT and PIM-2–/– mice were cocultured with allogeneic antigen-presenting cells from B6 mice for 5 days in the presence or absence of anti–IL-9R. (D) IL-9R expression was measured on T cells (n = 4). (E) Cells were restimulated with PMA and ionomycin for IFN-γ secretion. Percentages of CFSE-diluted and IFN-γ–producing cells on gated live donor CD4+ or CD8+ T cells (n = 4). Data represent mean ± SEM by 2-tailed Student’s t test (C), Mann-Whitney test (D), and 1-way ANOVA and Tukey’s HSD post hoc analysis (E). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.