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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...

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Autores principales: Zhao, Xin, Chen, Xiaojuan, Shen, Xinghua, Tang, Peijun, Chen, Chen, Zhu, Qitai, Li, Muyao, Xia, Rui, Yang, Xi, Feng, Chao, Zhu, Xinguo, Zhu, Yibei, Sun, Zhongwen, Zhang, Xueguang, Lu, Binfeng, Wang, Xuefeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
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
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author Zhao, Xin
Chen, Xiaojuan
Shen, Xinghua
Tang, Peijun
Chen, Chen
Zhu, Qitai
Li, Muyao
Xia, Rui
Yang, Xi
Feng, Chao
Zhu, Xinguo
Zhu, Yibei
Sun, Zhongwen
Zhang, Xueguang
Lu, Binfeng
Wang, Xuefeng
author_facet Zhao, Xin
Chen, Xiaojuan
Shen, Xinghua
Tang, Peijun
Chen, Chen
Zhu, Qitai
Li, Muyao
Xia, Rui
Yang, Xi
Feng, Chao
Zhu, Xinguo
Zhu, Yibei
Sun, Zhongwen
Zhang, Xueguang
Lu, Binfeng
Wang, Xuefeng
author_sort Zhao, Xin
collection PubMed
description 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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spelling pubmed-66924582019-08-23 IL-36β Promotes CD8(+) T Cell Activation and Antitumor Immune Responses by Activating mTORC1 Zhao, Xin Chen, Xiaojuan Shen, Xinghua Tang, Peijun Chen, Chen Zhu, Qitai Li, Muyao Xia, Rui Yang, Xi Feng, Chao Zhu, Xinguo Zhu, Yibei Sun, Zhongwen Zhang, Xueguang Lu, Binfeng Wang, Xuefeng Front Immunol Immunology 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. Frontiers Media S.A. 2019-08-07 /pmc/articles/PMC6692458/ /pubmed/31447838 http://dx.doi.org/10.3389/fimmu.2019.01803 Text en Copyright © 2019 Zhao, Chen, Shen, Tang, Chen, Zhu, Li, Xia, Yang, Feng, Zhu, Zhu, Sun, Zhang, Lu and Wang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Zhao, Xin
Chen, Xiaojuan
Shen, Xinghua
Tang, Peijun
Chen, Chen
Zhu, Qitai
Li, Muyao
Xia, Rui
Yang, Xi
Feng, Chao
Zhu, Xinguo
Zhu, Yibei
Sun, Zhongwen
Zhang, Xueguang
Lu, Binfeng
Wang, Xuefeng
IL-36β Promotes CD8(+) T Cell Activation and Antitumor Immune Responses by Activating mTORC1
title IL-36β Promotes CD8(+) T Cell Activation and Antitumor Immune Responses by Activating mTORC1
title_full IL-36β Promotes CD8(+) T Cell Activation and Antitumor Immune Responses by Activating mTORC1
title_fullStr IL-36β Promotes CD8(+) T Cell Activation and Antitumor Immune Responses by Activating mTORC1
title_full_unstemmed IL-36β Promotes CD8(+) T Cell Activation and Antitumor Immune Responses by Activating mTORC1
title_short IL-36β Promotes CD8(+) T Cell Activation and Antitumor Immune Responses by Activating mTORC1
title_sort il-36β promotes cd8(+) t cell activation and antitumor immune responses by activating mtorc1
topic Immunology
url 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
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