AIM2 in regulatory T cells restrains autoimmune diseases
NATURE(2021)
Abstract
The inflammasome initiates innate defence and inflammatory responses by activating caspase-1 and pyroptotic cell death in myeloid cells 1 , 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 cells 3 – 6 . Here we show that the DNA-binding inflammasome receptor AIM2 7 – 10 has a T cell-intrinsic and inflammasome-independent role in the function of T regulatory (T reg ) cells. AIM2 is highly expressed by both human and mouse T reg cells, is induced by TGFβ, and its promoter is occupied by transcription factors that are associated with T reg 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 T reg cells. Mechanistically, AIM2 interacts with the RACK1–PP2A phosphatase complex to restrain AKT phosphorylation. Lineage-tracing analysis demonstrates that AIM2 promotes the stability of T reg 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 T reg cells.
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Key words
Autoimmunity,Immunology,Science,Humanities and Social Sciences,multidisciplinary
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