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IL-36? Promotes CD8+ T Cell Activation and Antitumor Immune Responses by Activating mTORC1.


ABSTRACT: Cytokine-amplified functional CD8+ T cells ensure effective eradication of tumors. Interleukin 36? (IL-36?), IL-36?, and IL-36? share the same receptor complex, composed of the IL-36 receptor (IL-36R), and IL-1RAcP. Recently, we revealed that IL-36? 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-36? had the same effect on CD8+ T cell as IL-36?, and uncovered that IL-36? significantly activated mammalian target of rapamycin complex 1 (mTORC1) of CD8+ T cells. When mTORC1 was inhibited by rapamycin, IL-36?-stimulated CD8+ T cell activation and expansion was drastically downregulated. Further, we elucidated that IL-36?-mediated mTORC1 activation was dependent on the pathway of phosphatidylinositol 3 kinase (PI3K)/Akt, I?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? 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? 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? into tumor immunotherapy.

SUBMITTER: Zhao X 

PROVIDER: S-EPMC6692458 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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IL-36β Promotes CD8<sup>+</sup> T Cell Activation and Antitumor Immune Responses by Activating mTORC1.

Zhao Xin X   Chen Xiaojuan X   Shen Xinghua X   Tang Peijun P   Chen Chen C   Zhu Qitai Q   Li Muyao M   Xia Rui R   Yang Xi X   Feng Chao C   Zhu Xinguo X   Zhu Yibei Y   Sun Zhongwen Z   Zhang Xueguang X   Lu Binfeng B   Wang Xuefeng X  

Frontiers in immunology 20190807


Cytokine-amplified functional CD8<sup>+</sup> 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<sup>+</sup> T cell activation, contributing to antitumor immune responses. However, the underlying mechanism of IL-36-mediated CD8<sup>+</sup> T cell activation remains understood. In the current study, we proved that  ...[more]

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