Deficiency of the innate immune adaptor STING promotes autoreactive T cell expansion in NOD mice
- 23 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Diabetologia
- Vol. 64 (4), 878-889
- https://doi.org/10.1007/s00125-020-05378-z
Abstract
Aims/hypothesis Stimulator of IFN genes (STING) is a central hub for cytosolic nucleic acid sensing and its activation results in upregulation of type I IFN production in innate immune cells. A type I IFN gene signature seen before the onset of type 1 diabetes has been suggested as a driver of disease initiation both in humans and in the NOD mouse model. A possible source of type I IFN is through activation of the STING pathway. Recent studies suggest that STING also has antiproliferative and proapoptotic functions in T cells that are independent of IFN. To investigate whether STING is involved in autoimmune diabetes, we examined the impact of genetic deletion of STING in NOD mice. Methods CRISPR/Cas9 gene editing was used to generate STING-deficient NOD mice. Quantitative real-time PCR was used to assess the level of type I IFN-regulated genes in islets from wild-type and STING-deficient NOD mice. The number of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)206-214-specific CD8+ T cells was determined by magnetic bead-based MHC tetramer enrichment and flow cytometry. The incidence of spontaneous diabetes and diabetes after adoptive transfer of T cells was determined. Results STING deficiency partially attenuated the type I IFN gene signature in islets but did not suppress insulitis. STING-deficient NOD mice accumulated an increased number of IGRP206-214-specific CD8+ T cells (2878 ± 642 cells in NOD.STING−/− mice and 728.8 ± 196 cells in wild-type NOD mice) in peripheral lymphoid tissue, associated with a higher incidence of spontaneous diabetes (95.5% in NOD.STING−/− mice and 86.2% in wild-type NOD mice). Splenocytes from STING-deficient mice rapidly induced diabetes after adoptive transfer into irradiated NOD recipients (median survival 75 days for NOD recipients of NOD.STING−/− mouse splenocytes and 121 days for NOD recipients of NOD mouse splenocytes). Conclusions/interpretation Data suggest that sensing of endogenous nucleic acids through the STING pathway may be partially responsible for the type I IFN gene signature but not autoimmunity in NOD mice. Our results show that the STING pathway may play an unexpected intrinsic role in suppressing the number of diabetogenic T cells. Graphical abstractFunding Information
- Manpei Suzuki Diabetes Foundation
- National Health and Medical Research Council (GNT1150425)
- Juvenile Diabetes Research Foundation International (3-PDF-2017-379-A-N)
This publication has 49 references indexed in Scilit:
- Early-life factors contributing to type 1 diabetesDiabetologia, 2019
- cGAS in action: Expanding roles in immunity and inflammationScience, 2019
- Intracellular Nucleic Acid Detection in AutoimmunityAnnual Review of Immunology, 2017
- Regulation and function of the cGAS–STING pathway of cytosolic DNA sensingNature Immunology, 2016
- The host STING pathway at the interface of cancer and immunityJCI Insight, 2016
- Environmental risk factors for type 1 diabetesThe Lancet, 2016
- STING: infection, inflammation and cancerNature Reviews Immunology, 2015
- Lessons from the mouse: potential contribution of bystander lymphocyte activation by viruses to human type 1 diabetesDiabetologia, 2015
- Viral infections as potential triggers of type 1 diabetesDiabetes/Metabolism Research and Reviews, 2007
- Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locusNature Genetics, 2006