TY - JOUR
T1 - AIM2 in regulatory T cells restrains autoimmune diseases
AU - Chou, Wei-Chun
AU - Guo, Zengli
AU - Guo, Hao
AU - Chen, Liang
AU - Zhang, Ge
AU - Liang, Kaixin
AU - Xie, Ling
AU - Tan, Xianming
AU - Gibson, Sara A.
AU - Rampanelli, Elena
AU - Wang, Yan
AU - Montgomery, Stephanie A.
AU - Brickey, W. June
AU - Deng, Meng
AU - Freeman, Leslie
AU - Zhang, Song
AU - Su, Maureen A.
AU - Chen, Xian
AU - Wan, Yisong Y.
AU - Ting, Jenny P. -Y.
N1 - Funding Information: Acknowledgements The following funding supports are acknowledged: NIH (AI029564, CA156330, DK094779, AI097392, AI123193), the National Multiple Sclerosis Society (CA10068 to J.P.-Y.T. and FG 1968-A-1 to W.C.), NIAID (AI067798 to J.P.-Y.T., H.G. and W.J.B.), the National Multiple Sclerosis Society (RG-1802-30483), and a Yang Family Biomedical Scholars Award to Y.Y.W. We received help from G.D. Sempowski (Duke University, Duke Human Vaccine Institute, Durham, NC, USA, Immune Monitoring Core for AI067798) for the Luminex assay and analysis. We thank B. Sartor (P01-DK094779) for advice regarding the colitis model, N. Fisher and J. Dow (UNC flow cytometry facility supported in part by P30 CA016086 Cancer Center Core Support Grant) for cell sorting, and Dale Cowley (UNC Animal Models Core for P30 CA016086) for generating Aim2fl/fl mice. This work benefitted from a publicly available online database assembled by the ImmGen consortium and The European Bioinformatics Institute (EMBL-EBI) without prior permission. We thank E. Holley-Guthrie for genotyping mice. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/3/11
Y1 - 2021/3/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85099850169&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41586-021-03231-w
DO - https://doi.org/10.1038/s41586-021-03231-w
M3 - Article
C2 - 33505023
SN - 0028-0836
VL - 591
SP - 300
EP - 305
JO - NATURE
JF - NATURE
IS - 7849
ER -