Differential controls of MAIT cell effector polarization by mTORC1/mTORC2 via integrating cytokine and costimulatory signals

• Published in: Nature communications Vol. 12; no. 1; p. 2029
• Main Authors: Tao, Huishan, Pan, Yun, Chu, Shuai, Li, Lei, Xie, Jinhai, Wang, Peng, Zhang, Shimeng, Reddy, Srija, Sleasman, John W., Zhong, Xiao-Ping
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/21; 13/31; 13/95; 45/77; 45/91; 631/136/2091; 631/250/127/1213; 631/250/1619/554; 631/553/1833; 64/60; Animals; Cell differentiation; Cell Differentiation - immunology; Cell growth; Cell proliferation; Cell survival; Cells, Cultured; Cytokines; Cytokines - immunology; Cytokines - metabolism; Differentiation; Homeostasis; Humanities and Social Sciences; Humans; IL-1β; Immune response; Immunology; Inducible T-Cell Co-Stimulator Protein - immunology; Inducible T-Cell Co-Stimulator Protein - metabolism; Interleukin 15; Interleukin 15 receptors; Interleukin 17; Interleukin 2; Interleukin 23; Interleukin-15 - immunology; Interleukin-15 - metabolism; Interleukin-2 - immunology; Interleukin-2 - metabolism; Invariants; Kinases; Ligands; Lymphocyte Activation - immunology; Lymphocytes; Mechanistic Target of Rapamycin Complex 1 - immunology; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mechanistic Target of Rapamycin Complex 2 - immunology; Mechanistic Target of Rapamycin Complex 2 - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mucosa; Mucosal-Associated Invariant T Cells - cytology; Mucosal-Associated Invariant T Cells - immunology; Mucosal-Associated Invariant T Cells - metabolism; multidisciplinary; Pathogens; Polarization; Roles; Science; Science (multidisciplinary); Signal Transduction - immunology; Thymus gland; TOR protein; TOR Serine-Threonine Kinases - immunology; TOR Serine-Threonine Kinases - metabolism; Transcription factors; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22162-8

Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage differentiation remain unclear. Here, we report that IL-2/IL-15 receptor β chain and inducible costimulatory (ICOS) not only serve as lineage-specific markers for IFN-γ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are also important for their differentiation, respectively. Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. By contrast, IL-1β induces more MAIT17 than MAIT1 cells, while IL-23 alone promotes MAIT17 cell proliferation and survival, but synergizes with IL-1β to induce strong MAIT17 cell expansion in an mTOR-dependent manner. Moreover, mTOR is dispensable for early MAIT cell development, yet pivotal for MAIT cell effector differentiation. Our results thus show that mTORC2 integrates signals from ICOS and IL-1βR/IL-23R to exert a crucial role for MAIT17 differentiation, while the IL-2/IL-15R-mTORC1-T-bet axis ensures MAIT1 differentiation. Mucosal-associated invariant T (MAIT) cells are key in immunity and diseases, but how their effector polarization is controlled is still unclear. Here, the authors show that an IL-1β/IL-23/mTORC2 axis is essential for the induction of IL-17-producing MAIT17, while an IL-2/IL-15/mTORC1 axis is important for the homeostasis of IFN-γ-producing MAIT1.