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

Cytokine-amplified functional CD8(+) T cells ensure effective eradication of tumors. Interleukin 36 alpha (IL-36 alpha), IL-36 beta, and IL-36 gamma share the same receptor complex, composed of the IL-36 receptor (IL-36R), and IL-1RAcP. Recently, we revealed that IL-36 gamma greatly promoted CD8(+) T cell activation, contributing to antitumor immune responses. However, the underlyingmechanismof IL-36-mediated CD8(+) T cell activation remains understood. In the current study, we proved that IL-36 beta had the same effect on CD8(+) T cell as IL-36 gamma, and uncovered that IL-36 beta significantly activated mammalian target of rapamycin complex 1 (mTORC1) of CD8(+) T cells. When mTORC1 was inhibited by rapamycin, IL-36 beta-stimulated CD8(+) T cell activation and expansion was drastically downregulated. Further, we elucidated that IL-36 beta-mediated mTORC1 activation was dependent on the pathway of phosphatidylinositol 3 kinase (PI3K)/Akt, I k B 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-36 beta 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-36 beta 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-36 beta into tumor immunotherapy.