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

Huishan Tao, Yun Pan, Shuai Chu, Lei Li, Jinhai Xie, Peng Wang, Shimeng Zhang, Srija Reddy, John W. Sleasman and Xiao-Ping Zhong ()
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Huishan Tao: Duke University Medical Center
Yun Pan: Duke University Medical Center
Shuai Chu: Duke University Medical Center
Lei Li: Duke University Medical Center
Jinhai Xie: Duke University Medical Center
Peng Wang: Duke University Medical Center
Shimeng Zhang: Duke University Medical Center
Srija Reddy: Duke University Medical Center
John W. Sleasman: Duke University Medical Center
Xiao-Ping Zhong: Duke University Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-21

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22162-8

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