AIM2 in regulatory T cells restrains autoimmune diseases

Abstract The inflammasome comprised of an innate immune receptor/sensor, pro-caspase-1, and a common adaptor molecule, ASC (apoptotic speck-containing protein with CARD) initiates defense inflammatory response by activating caspase-1 pyroptotic cell death in myeloid cells. Consistent their pro-inflammatory function, caspase-1, NLRP3 were known to exacerbate autoimmunity during experimental autoimmune encephalomyelitis (EAE) enhancing IL-1b IL-18 secretion Here we reveal unexpected function DNA-binding receptor, AIM2 (Absent Melanoma 2), T regulatory cells (Tregs) restrain two models disease, including cell-mediated colitis, studying whole-body Treg-specific Aim2-deficient mice. is highly expressed human mouse Tregs, its expression induced TGF-b promoter occupied transcription factors associated Runx1, Ets1, Bcl11b CREB. Moreover, demonstrate that promotes the stability Tregs inflammation lineage tracing RNA-seq, biochemical metabolic analyses revealed attenuates Akt-phosphorylation, mTOR, Myc glycolysis, but lipid oxidative phosphorylation Tregs. Mechanistically, interacts RACK1/PP2A-phosphatase complex Akt-phosphorylation. While generally accepted as effector cells, this report unveils cell-intrinsic role restraining diminishing Akt-mTOR signaling altering immune-metabolism enhance Treg stability.