PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity
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Daenthanasanmak, AnusaraWu, Yongxia
Iamsawat, Supinya
Nguyen, Hung D.
Bastian, David
Zhang, MengMeng
Sofi, M. Hanief
Chatterjee, Shilpak
Hill, Elizabeth G.
Mehrotra, Shikhar
Kraft, Andrew S.
Yu, Xue-Zhong
Affiliation
Univ Arizona, Ctr CancIssue Date
2018-07-02
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AMER SOC CLINICAL INVESTIGATION INCCitation
J Clin Invest. 2018;128(7):2787-2801. https://doi.org/10.1172/JCI95407.Rights
Copyright © 2018, American Society for Clinical Investigation.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.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.ISSN
0021-97381558-8238
PubMed ID
29781812Version
Final published versionSponsors
Biostatistics Shared Resource, Hollings Cancer Center, Medical University of South Carolina [P30 CA138313]; University of Arizona Cancer Center [P30 CA023074]; NIH [R01CA173200, R01 CA169116, R01 AI118305, R01 HL137373, R21 CA192202]; DOD [W81XWH-12-1-0560]; SmartState Endowment in Cancer Stem Cell Biology & Therapy Programae974a485f413a2113503eed53cd6c53
10.1172/JCI95407
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