Deficiency of the innate immune adaptor STING promotes autoreactive T cell expansion in NOD mice

• Published in: Diabetologia 2021-04, Vol.64 (4), p.878-889
• Main Authors: Akazawa, Satoru, Mackin, Leanne, Jhala, Gaurang, Fynch, Stacey, Catterall, Tara, Selck, Claudia, Graham, Kate L., Krishnamurthy, Balasubramanian, Pappas, Evan G., Kwong, Chun-Ting J., Sutherland, Andrew P. R., Kay, Thomas W. H., Brodnicki, Thomas C., Thomas, Helen E.
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Apoptosis; Autoimmune diseases; Autoimmunity; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - transplantation; Cell Proliferation; CRISPR; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - metabolism; Disease Models, Animal; Female; Flow cytometry; Gene deletion; Gene Expression Regulation; Genes; Genome editing; Glucose-6-phosphatase; Human Physiology; Insulitis; Interferon; Internal Medicine; Islets of Langerhans - immunology; Islets of Langerhans - metabolism; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Lymphoid tissue; Major histocompatibility complex; Male; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolic Diseases; Mice; Mice, Inbred NOD; Mice, Knockout; Rodents; Signal Transduction; Splenocytes
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-020-05378-z

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 IGRP 206-214 -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 abstract