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 4

PIM-2 kinase suppresses T cell differentiation into Th1 cells, T cell migration, and GVHD pathogenicity.

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PIM-2 kinase suppresses T cell differentiation into Th1 cells, T cell mi...
(A–C) Seven days after GVHD induction, spleen, liver, and gut were collected from the recipient mice, and the resulting cell suspension was analyzed by flow cytometry. (A) Representative dot plots show percentages of CXCR3 and α4β7 expression on gated donor CD4+ or CD8+ T cells in recipients’ spleens. (B) The percentages of IFN-γ–, IL-4/5–, or IL-17–secreting cells are shown on gated donor CD4+ and CD8+ T cells in recipients’ livers. The absolute number of IFN-γ among donor T cells is depicted. (C) The frequency of IFN-γ, IL-4/5, IL-17, and Ki67 among isolated donor T cells from recipients’ intestines. Data are representative of 2 independent experiments (n = 7–10 mice per group) and are shown as mean ± SEM by 1-way ANOVA and Tukey’s HSD post hoc analysis. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.