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

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

doi:10.18632/oncotarget.15403

Daisuke Muraoka, Kana Okamori + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.15403

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Journal: Oncotarget	Publication Date: Feb 16, 2017
Citations: 9	License type: cc-by

Affiliation: Mie University, University of Shizuoka

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.

Highlights

Memory CD8+ cytotoxic T lymphocytes (CTLs) play a central role in infection prophylaxis and surveillance against malignancy [1, 2]
By signal-transducing adaptor protein-2 (STAP2) knockdown in antigen-experienced CD8+ T cells, we demonstrated that STAP2 was dispensable during the effector phase but was essential for the formation of functional memory CD8+ T cells and their recall responses in a T cell-intrinsic manner
STAP2 deficiency resulted in impaired cytotoxicity and cytokine production from memory CTLs in association with attenuation of STAT3 signaling

Summary

Introduction

Memory CD8+ CTLs play a central role in infection prophylaxis and surveillance against malignancy [1, 2]. Specific cytokine signals regulate CD8+ T cell differentiation and memory formation as follows: IL-7 and IL-15 promote CD8+ memory T cell survival and self-renewal [13], IL-2 controls the balance of memory and effector T cell differentiation by regulating eomesodermin (Eomes) expression [5], and IL-10 and IL-21 signals are crucial for the formation of mature self-renewing memory T cells in a B cell lymphoma-6-mediated manner [14]. STATs play an essential role in the regulation of CD8+ memory T cell differentiation via cytokine signaling and cytokine production in antigen-stimulated CD8+ T cells. During memory T cell differentiation, STAT5 or STAT3 is required for signaling via IL-2, IL-7, and IL-15, or IL-10 and IL-21, respectively [5], [14,15,16], SOCS family proteins act as an intracellular regulator of STAT signals. The molecular mechanisms regulating these signals by intracellular molecules such as adaptor proteins remain to be elucidated

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