2. Academic Validation
  3. IL-36β Promotes CD8+ T Cell Activation and Antitumor Immune Responses by Activating mTORC1

IL-36β Promotes CD8+ T Cell Activation and Antitumor Immune Responses by Activating mTORC1

  • Front Immunol. 2019 Aug 7;10:1803. doi: 10.3389/fimmu.2019.01803.
Xin Zhao 1 2 3 4 5,  Xiaojuan Chen 3 4 5 6,  Xinghua Shen 7,  Peijun Tang 7,  Chen Chen 2,  Qitai Zhu 2,  Muyao Li 2,  Rui Xia 8,  Xi Yang 9,  Chao Feng 10,  Xinguo Zhu 1,  Yibei Zhu 3 4 5 11,  Zhongwen Sun 12,  Xueguang Zhang 3 4 5,  Binfeng Lu 13,  Xuefeng Wang 2 3 4 5
Affiliations

Affiliations

  • 1 Department of General Surgery, The First Affiliated Hospital, Soochow University, Suzhou, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
  • 3 Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 4 Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.
  • 5 Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 6 Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 7 Department of Pulmonary Tuberculosis, The Affiliated Hospital for Infectious Diseases of Soochow University, Suzhou, China.
  • 8 Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
  • 9 School of Medicine, Tsinghua University, Peking, China.
  • 10 Institute of Translational Medicine, Soochow University, Suzhou, China.
  • 11 Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China.
  • 12 Institute of Medical Biotechnology, Suzhou Vocational Health College, Vocational Health College, Suzhou, China.
  • 13 Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
PMID: 31447838 DOI: 10.3389/fimmu.2019.01803
Abstract

Cytokine-amplified functional CD8+ T cells ensure effective eradication of tumors. Interleukin 36α (IL-36α), IL-36β, and IL-36γ share the same receptor complex, composed of the IL-36 receptor (IL-36R), and IL-1RAcP. Recently, we revealed that IL-36γ greatly promoted CD8+ T cell activation, contributing to antitumor immune responses. However, the underlying mechanism of IL-36-mediated CD8+ T cell activation remains understood. In the current study, we proved that IL-36β had the same effect on CD8+ T cell as IL-36γ, and uncovered that IL-36β significantly activated mammalian target of rapamycin complex 1 (mTORC1) of CD8+ T cells. When mTORC1 was inhibited by rapamycin, IL-36β-stimulated CD8+ T cell activation and expansion was drastically downregulated. Further, we elucidated that IL-36β-mediated mTORC1 activation was dependent on the pathway of phosphatidylinositol 3 kinase (PI3K)/Akt, IκB kinase (IKK) and myeloid differentiation factor 88 (MyD88). Inhibition of PI3K or IKK by inhibitor, or deficiency of MyD88, respectively, suppressed mTORC1 signal, causing arrest of CD8+ T cell activation. Additionally, it was validated that IL-36β significantly promoted mTORC1 activation and antitumor function of CD8+ tumor-infiltrating lymphocytes (TILs) in vivo, resulting in inhibition of tumor growth and prolongation of survival of tumor-bearing mice. Taken together, we substantiated that IL-36β could promote CD8+ T cell activation through activating mTORC1 dependent on PI3K/Akt, IKK and MyD88 pathways, leading to enhancement of antitumor immune responses, which laid the foundations for applying IL-36β into tumor immunotherapy.

Keywords

CD8+ T cells; IL-36β; antitumor immune responses; mTORC1; tumor microenvironment.

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