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

Oncotarget. 2017 May 9;8(19):30766-30780. doi: 10.18632/oncotarget.15403.

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.

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antigens, Neoplasm / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation / immunology
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Immunologic Memory*
  • Lymphocyte Activation / immunology
  • Membrane Proteins / immunology
  • Mice
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction*
  • Spleen / immunology
  • Suppressor of Cytokine Signaling 3 Protein / metabolism
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism
  • Vaccines, DNA / immunology
  • Vaccines, Subunit / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Neoplasm
  • CTAG1B protein, human
  • Epitopes, T-Lymphocyte
  • Membrane Proteins
  • STAP2 protein, mouse
  • STAT3 Transcription Factor
  • Suppressor of Cytokine Signaling 3 Protein
  • Vaccines, DNA
  • Vaccines, Subunit