AIM2 in regulatory T cells restrains autoimmune diseases

Wei-Chun Chou, Zengli Guo, Hao Guo, Liang Chen, Ge Zhang, Kaixin Liang, Ling Xie, Xianming Tan, Sara A. Gibson, Elena Rampanelli, Yan Wang, Stephanie A. Montgomery, W. June Brickey, Meng Deng, Leslie Freeman, Song Zhang, Maureen A. Su, Xian Chen, Yisong Y. Wan () and Jenny P.-Y. Ting ()
Additional contact information
Wei-Chun Chou: University of North Carolina at Chapel Hill
Zengli Guo: University of North Carolina at Chapel Hill
Hao Guo: University of North Carolina at Chapel Hill
Liang Chen: University of North Carolina at Chapel Hill
Ge Zhang: University of North Carolina at Chapel Hill
Kaixin Liang: University of North Carolina at Chapel Hill
Ling Xie: University of North Carolina at Chapel Hill
Xianming Tan: University of North Carolina at Chapel Hill
Sara A. Gibson: University of North Carolina at Chapel Hill
Elena Rampanelli: University of North Carolina at Chapel Hill
Yan Wang: University of North Carolina at Chapel Hill
Stephanie A. Montgomery: University of North Carolina at Chapel Hill
W. June Brickey: University of North Carolina at Chapel Hill
Meng Deng: University of North Carolina at Chapel Hill
Leslie Freeman: University of North Carolina at Chapel Hill
Song Zhang: University of North Carolina at Chapel Hill
Maureen A. Su: University of North Carolina at Chapel Hill
Xian Chen: University of North Carolina at Chapel Hill
Yisong Y. Wan: University of North Carolina at Chapel Hill
Jenny P.-Y. Ting: University of North Carolina at Chapel Hill

Nature, 2021, vol. 591, issue 7849, 300-305

Abstract: Abstract The inflammasome initiates innate defence and inflammatory responses by activating caspase-1 and pyroptotic cell death in myeloid cells1,2. It consists of an innate immune receptor/sensor, pro-caspase-1, and a common adaptor molecule, ASC. Consistent with their pro-inflammatory function, caspase-1, ASC and the inflammasome component NLRP3 exacerbate autoimmunity during experimental autoimmune encephalomyelitis by enhancing the secretion of IL-1β and IL-18 in myeloid cells3–6. Here we show that the DNA-binding inflammasome receptor AIM27–10 has a T cell-intrinsic and inflammasome-independent role in the function of T regulatory (Treg) cells. AIM2 is highly expressed by both human and mouse Treg cells, is induced by TGFβ, and its promoter is occupied by transcription factors that are associated with Treg cells such as RUNX1, ETS1, BCL11B and CREB. RNA sequencing, biochemical and metabolic analyses demonstrated that AIM2 attenuates AKT phosphorylation, mTOR and MYC signalling, and glycolysis, but promotes oxidative phosphorylation of lipids in Treg cells. Mechanistically, AIM2 interacts with the RACK1–PP2A phosphatase complex to restrain AKT phosphorylation. Lineage-tracing analysis demonstrates that AIM2 promotes the stability of Treg cells during inflammation. Although AIM2 is generally accepted as an inflammasome effector in myeloid cells, our results demonstrate a T cell-intrinsic role of AIM2 in restraining autoimmunity by reducing AKT–mTOR signalling and altering immune metabolism to enhance the stability of Treg cells.

Date: 2021
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DOI: 10.1038/s41586-021-03231-w

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