Oncotarget

Research Papers: Immunology:

Signal-transducing adaptor protein-2 promotes generation of functional long-term memory CD8+ T cells by preventing terminal effector differentiation

Daisuke Muraoka _, Naohiro Seo, Tae Hayashi, Chisaki Hyuga-Amaike, Kana Okamori, Isao Tawara, Naozumi Harada and Hiroshi Shiku

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Oncotarget. 2017; 8:30766-30780. https://doi.org/10.18632/oncotarget.15403

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Abstract

Daisuke Muraoka1,2, Naohiro Seo1, Tae Hayashi1, Chisaki Hyuga-Amaike1, Kana Okamori1, Isao Tawara3, Naozumi Harada1 and Hiroshi Shiku1

1 Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan

2 Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan

3 Department of Hematology and Oncology, Mie University Graduate School of Medicine, Mie, Japan

Correspondence to:

Daisuke Muraoka, email:

Hiroshi Shiku, email:

Keywords: memory T cell, CTL function, STAP2, STAT signaling, SOCS3, Immunology and Microbiology Section, Immune response, Immunity

Received: April 18, 2016 Accepted: February 01, 2017 Published: February 16, 2017

Abstract

Long-surviving memory CD8+ T cells generated by stimulation with appropriate tumor-associated antigens are the most aggressive and persistent tumoricidal effectors. In this event of memory CD8+ T cell development, the signal transducer and activator of transcription (STAT) proteins function as the crucial intracellular signaling molecules, but the regulatory mechanism of STATs in CD8+ T cells is not fully understood. In this study, we report for the first time, by using murine vaccination models, that signal-transducing adaptor protein-2 (STAP2) maintains the cytotoxicity of long-lived memory CD8+ T cells by controlling a STAT3/suppressor of cytokine signaling 3 (SOCS3) cascade. Following T cell activation, STAP2 expression was transiently reduced but was subsequently recovered and augmented. Analysis using small-interfering RNA (siRNA) demonstrated that restored STAP2 expression was associated with the activation of STAT3/SOCS3 signals and maintenance of cytotoxic T lymphocytes (CTLs) secondary responses by preventing their differentiation into terminal effector cells. Notably, this STAP2-dependent memory differentiation was observed in the spleen, but not in the lymph nodes (LNs). These findings indicate an essential role for STAP2 in the generation of a high-quality memory CD8+ CTLs periphery, and suggest the therapeutic potential of STAP2 in cancer patients.


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