The histone demethylase Utx controls <scp>CD8</scp><sup>+</sup> T‐cell‐dependent antitumor immunity via epigenetic regulation of the effector function

DOI Web Site 参考文献48件
  • Haruna Noda
    Breast Center Ehime University Hospital Toon Japan
  • Junpei Suzuki
    Department of Immunology, Graduate School of Medicine Ehime University Toon Japan
  • Yuko Matsuoka
    Department of Translational Research Center Ehime University Hospital Toon Japan
  • Akira Matsumoto
    Department of Infections and Host Defenses, Graduate School of Medicine Ehime University Toon Japan
  • Makoto Kuwahara
    Department of Immunology, Graduate School of Medicine Ehime University Toon Japan
  • Yoshiaki Kamei
    Breast Center Ehime University Hospital Toon Japan
  • Yasutsugu Takada
    Department of Hepato‐Biliary‐Pancreatic Surgery and Breast Surgery, Graduate School of Medicine Ehime University Toon Japan
  • Masakatsu Yamashita
    Department of Immunology, Graduate School of Medicine Ehime University Toon Japan

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<jats:title>Abstract</jats:title><jats:p>CD8<jats:sup>+</jats:sup> T cells play a central role in antitumor immune responses. Epigenetic gene regulation is essential to acquire the effector function of CD8<jats:sup>+</jats:sup> T cells. However, the role of <jats:italic>Utx</jats:italic>, a demethylase of histone H3K27, in antitumor immunity remains unclear. In this study, we examined the roles of <jats:italic>Utx</jats:italic> in effector CD8<jats:sup>+</jats:sup> T‐cell differentiation and the antitumor immune response. In a murine tumor‐bearing model, an increased tumor size and decreased survival rate were observed in T‐cell‐specific <jats:italic>Utx</jats:italic> KO (<jats:italic>Utx</jats:italic> KO) mice compared with wild‐type (WT) mice. The number of CD8<jats:sup>+</jats:sup> T cells in tumor‐infiltrating lymphocytes (TILs) was significantly decreased in <jats:italic>Utx</jats:italic> KO mice. We found that the acquisition of effector function was delayed and attenuated in <jats:italic>Utx</jats:italic> KO CD8<jats:sup>+</jats:sup> T cells. RNA sequencing revealed that the expression of effector signature genes was decreased in <jats:italic>Utx</jats:italic> KO effector CD8<jats:sup>+</jats:sup> T cells, while the expression of naïve or memory signature genes was increased. Furthermore, the expression of Cxcr3, which is required for the migration of effector CD8<jats:sup>+</jats:sup> T cells to tumor sites, was substantially decreased in <jats:italic>Utx</jats:italic> KO CD8<jats:sup>+</jats:sup> T cells. These findings suggest that <jats:italic>Utx</jats:italic> promotes CD8<jats:sup>+</jats:sup> T‐cell‐dependent antitumor immune responses partially through epigenetic regulation of the effector function.</jats:p>

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