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 2

PIM-2 expression inhibits T cell proliferation and Th1 differentiation under allogeneic stimulation in vitro and in vivo.

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PIM-2 expression inhibits T cell proliferation and Th1 differentiation u...
(A and B) In vitro mix lymphocyte reaction. Purified T cells of WT, PIM-2–/–, and PIM-1/3–/– mice on an FVB background (H-2q) were labeled with CFSE and cocultured with T cell–depleted splenocytes as antigen-presenting cells from B6 mice (H2b) for 5 days. Cells were restimulated with PMA and ionomycin for cytokine secretion. Percentages of CFSE-diluted and IFN-γ–producing cells on gated live donor CD4+ or CD8+ T cells (n = 6). (C) Purified T cells from WT, PIM-2–/–, and PIM-1/3–/– mice were labeled with CFSE and transferred into lethally irradiated BALB/c (H-2d) mice at 2 × 106 cells per mouse. Four days after cell transfer, recipient spleens and mLNs were harvested and analyzed by flow cytometry. Representative figures and percentages are shown on gated live cells followed by H-2q+ cells. (D) Percentages of donor T cells are shown in recipient spleen and mLNs. Average percentages of CFSE-diluted, IFN-γ+, IL-4/5+ cells are shown on gated live donor CD4+ or CD8+ T cells in recipient spleen (n = 4–5 mice per group). Data are representative of at least 2 independent experiments and are shown as mean ± SEM by 1-way ANOVA and Tukey’s HSD post hoc analysis (B and D). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.