| First Author | Akazawa S | Year | 2021 |
| Journal | Diabetologia | Volume | 64 |
| Issue | 4 | Pages | 878-889 |
| PubMed ID | 33483762 | Mgi Jnum | J:328887 |
| Mgi Id | MGI:6724636 | Doi | 10.1007/s00125-020-05378-z |
| Citation | Akazawa S, et al. (2021) Deficiency of the innate immune adaptor STING promotes autoreactive T cell expansion in NOD mice. Diabetologia 64(4):878-889 |
| abstractText | 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. |
