AUTHOR=Zhao Xin, Chen Xiaojuan, Shen Xinghua, Tang Peijun, Chen Chen, Zhu Qitai, Li Muyao, Xia Rui, Yang Xi, Feng Chao, Zhu Xinguo, Zhu Yibei, Sun Zhongwen, Zhang Xueguang, Lu Binfeng, Wang Xuefeng
TITLE=IL-36β Promotes CD8+ T Cell Activation and Antitumor Immune Responses by Activating mTORC1
JOURNAL=Frontiers in Immunology
VOLUME=10
YEAR=2019
URL=https://www.frontiersin.org/articles/10.3389/fimmu.2019.01803
DOI=10.3389/fimmu.2019.01803
ISSN=1664-3224
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.