AIM2 in regulatory T cells restrains autoimmune diseases

Nature. 2021 Mar;591(7849):300-305. doi: 10.1038/s41586-021-03231-w. Epub 2021 Jan 27.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity / immunology*
  • CARD Signaling Adaptor Proteins / deficiency
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / prevention & control*
  • Female
  • Glycolysis
  • Humans
  • Inflammasomes
  • Inflammation / immunology
  • Mice
  • Oxidative Phosphorylation
  • Phosphorylation
  • Protein Phosphatase 2 / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • Receptors for Activated C Kinase / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta


  • AIM2 protein, human
  • Aim2 protein, mouse
  • CARD Signaling Adaptor Proteins
  • DNA-Binding Proteins
  • Inflammasomes
  • Proto-Oncogene Proteins c-myc
  • Pycard protein, mouse
  • Receptors for Activated C Kinase
  • Transcription Factors
  • Transforming Growth Factor beta
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Protein Phosphatase 2