| First Author | Zhao X | Year | 2019 |
| Journal | Front Immunol | Volume | 10 |
| Pages | 1803 | PubMed ID | 31447838 |
| Mgi Jnum | J:288039 | Mgi Id | MGI:6415742 |
| Doi | 10.3389/fimmu.2019.01803 | Citation | Zhao X, et al. (2019) IL-36beta Promotes CD8(+) T Cell Activation and Antitumor Immune Responses by Activating mTORC1. Front Immunol 10:1803 |
| abstractText | Cytokine-amplified functional CD8(+) T cells ensure effective eradication of tumors. Interleukin 36alpha (IL-36alpha), IL-36beta, and IL-36gamma share the same receptor complex, composed of the IL-36 receptor (IL-36R), and IL-1RAcP. Recently, we revealed that IL-36gamma 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-36beta had the same effect on CD8(+) T cell as IL-36gamma, and uncovered that IL-36beta significantly activated mammalian target of rapamycin complex 1 (mTORC1) of CD8(+) T cells. When mTORC1 was inhibited by rapamycin, IL-36beta-stimulated CD8(+) T cell activation and expansion was drastically downregulated. Further, we elucidated that IL-36beta-mediated mTORC1 activation was dependent on the pathway of phosphatidylinositol 3 kinase (PI3K)/Akt, IkappaB 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-36beta 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-36beta 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-36beta into tumor immunotherapy. |
