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IL-36β Promotes CD8(+) T Cell Activation and Antitumor Immune Responses by Activating mTORC1
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, contr...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692458/ https://www.ncbi.nlm.nih.gov/pubmed/31447838 http://dx.doi.org/10.3389/fimmu.2019.01803 |
Sumario: | 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. |
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