%A Zhao,Xin %A Chen,Xiaojuan %A Shen,Xinghua %A Tang,Peijun %A Chen,Chen %A Zhu,Qitai %A Li,Muyao %A Xia,Rui %A Yang,Xi %A Feng,Chao %A Zhu,Xinguo %A Zhu,Yibei %A Sun,Zhongwen %A Zhang,Xueguang %A Lu,Binfeng %A Wang,Xuefeng %D 2019 %J Frontiers in Immunology %C %F %G English %K IL-36β,CD8+ T cells,mTORC1,Antitumor immune responses,Tumor Microenvironment %Q %R 10.3389/fimmu.2019.01803 %W %L %M %P %7 %8 2019-August-07 %9 Original Research %# %! IL-36β-triggered mTORC1 activation enhances CD8+ T cell function %* %< %T IL-36β Promotes CD8+ T Cell Activation and Antitumor Immune Responses by Activating mTORC1 %U https://www.frontiersin.org/articles/10.3389/fimmu.2019.01803 %V 10 %0 JOURNAL ARTICLE %@ 1664-3224 %X 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.