IL-36β Promotes CD8+ T Cell Activation and Antitumor Immune Responses by Activating mTORC1
IL-36β Promotes CD8+ T Cell Activation and Antitumor Immune Responses by Activating mTORC1
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IL-36 beta 通过激活 mTORC1 促进 CD8( ) T 细胞激活和抗肿瘤免疫反应
DOI：
10.3389/fimmu.2019.01803
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发表时间：
2019-08-07
影响因子：
7.3
通讯作者：
Wang, Xuefeng
中科院分区：
文献类型：
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作者：
Zhao, Xin;Chen, Xiaojuan;Wang, Xuefeng
细胞因子扩增的功能性CD 8（+）T细胞确保有效根除肿瘤。白细胞介素36 α（IL-36 α）、IL-36 β和IL-36 γ共享相同的受体复合物，由IL-36受体（IL-36 R）和IL-1 RAcP组成。最近，我们发现IL-36 γ极大地促进了CD 8（+）T细胞活化，有助于抗肿瘤免疫应答。然而，IL-36介导的CD 8（+）T细胞活化的潜在机制仍不清楚。在本研究中，我们证明了IL-36 β对CD 8（+）T细胞具有与IL-36 γ相同的作用，并且发现IL-36 β显著激活CD 8（+）T细胞的雷帕霉素复合物1（mTORC 1）。当mTORC 1被雷帕霉素抑制时，IL-36 β刺激的CD 8（+）T细胞活化和扩增急剧下调。此外，我们阐明了IL-36 β介导的mTORC 1激活依赖于磷脂酰肌醇3激酶（PI 3 K）/Akt、I k B激酶（IKK）和髓样分化因子88（MyD 88）途径。通过抑制剂抑制PI 3 K或IKK，或MyD 88缺乏，分别抑制mTORC 1信号，导致CD 8（+）T细胞活化停滞。此外，还证实了IL-36 β在体内可显著促进mTORC 1活化和CD 8（+）肿瘤浸润淋巴细胞（TIL）的抗肿瘤功能，从而抑制肿瘤生长并延长荷瘤小鼠的生存期。综上所述，我们证实了IL-36 β可通过激活mTORC 1依赖的PI 3 K/Akt、IKK和MyD 88通路促进CD 8（+）T细胞活化，从而增强抗肿瘤免疫应答，为IL-36 β应用于肿瘤免疫治疗奠定了基础。
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.