TY - JOUR AU - Zhao, Xin AU - Chen, Xiaojuan AU - Shen, Xinghua AU - Tang, Peijun AU - Chen, Chen AU - Zhu, Qitai AU - Li, Muyao AU - Xia, Rui AU - Yang, Xi AU - Feng, Chao AU - Zhu, Xinguo AU - Zhu, Yibei AU - Sun, Zhongwen AU - Zhang, Xueguang AU - Lu, Binfeng AU - Wang, Xuefeng PY - 2019 M3 - Original Research TI - IL-36β Promotes CD8+ T Cell Activation and Antitumor Immune Responses by Activating mTORC1 JO - Frontiers in Immunology UR - https://www.frontiersin.org/articles/10.3389/fimmu.2019.01803 VL - 10 SN - 1664-3224 N2 - 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. ER -