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


<jats:title>Abstract</jats:title><jats:p>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.</jats:p>






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Publication Info

Tao, Huishan, Yun Pan, Shuai Chu, Lei Li, Jinhai Xie, Peng Wang, Shimeng Zhang, Srija Reddy, et al. (2021). Differential controls of MAIT cell effector polarization by mTORC1/mTORC2 via integrating cytokine and costimulatory signals. Nature Communications, 12(1). 10.1038/s41467-021-22162-8 Retrieved from https://hdl.handle.net/10161/22530.

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John William Sleasman

Dr. Glenn A. Kiser and Eltha Muriel Kiser Professor of Pediatrics

Xiaoping Zhong

Professor of Pediatrics

The immune system protects the host from microbial infection but can cause diseases if not properly controlled. My lab is interested in the receptor signaling mediated regulation of immune cell development and function as well as the pathogenesis and treatment of autoimmune diseases and allergies.

We are currently investigating the roles diacylglycerol kinases (DGKs) and TSC1/2-mTOR play in the immune system. DGKs are a family of ten enzymes that catalyze the conversion of diacylglycerol (DAG) to phosphatidic acid (PA), Both DAG and PA are important second messengers involved signaling from numerous receptors. While we expect DGKs to perform important roles in development and cellular function by modulating DAG and PA levels, the physiologic functions of DGKs have been poorly understood. Using cell line models and genetically manipulated mice, we have demonstrated that DGKα and ζ isoforms play critical roles in: T cell development, activation, and anergy by regulating T cell receptor signaling; FcεRI signaling and mast cell function; and Toll-like receptor signaling and innate immune responses.

Research areas that we are actively pursuing include:
1. The mechanisms that control T cell maturation, activation
and self-tolerance.
2. NKT cell development and function.
3. Thymic epithelial cells and thymic development, function, and involution.
4. Regulation of Toll-like receptor signaling and innate immunity. 
5. The pathogenesis and treatment of autoimmune hepatitis. 
6. Mast cell development and function.
7. The pathogenesis and immunotherapy for peanut allergy.

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