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

// Daisuke Muraoka 1,2 , Naohiro Seo 1 , Tae Hayashi 1 , Chisaki Hyuga-Amaike 1 , Kana Okamori 1 , Isao Tawara 3 , Naozumi Harada 1 and Hiroshi Shiku 1 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.