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01-04-2021 | Type 1 Diabetes | Article

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

Authors: Satoru Akazawa, Leanne Mackin, Gaurang Jhala, Stacey Fynch, Tara Catterall, Claudia Selck, Kate L. Graham, Balasubramanian Krishnamurthy, Evan G. Pappas, Chun-Ting J. Kwong, Andrew P. R. Sutherland, Thomas W. H. Kay, Thomas C. Brodnicki, Helen E. Thomas

Published in: Diabetologia | Issue 4/2021

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 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

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Title: Deficiency of the innate immune adaptor STING promotes autoreactive T cell expansion in NOD mice
Authors: Satoru Akazawa
Leanne Mackin
Gaurang Jhala
Stacey Fynch
Tara Catterall
Claudia Selck
Kate L. Graham
Balasubramanian Krishnamurthy
Evan G. Pappas
Chun-Ting J. Kwong
Andrew P. R. Sutherland
Thomas W. H. Kay
Thomas C. Brodnicki
Helen E. Thomas
Publication date: 01-04-2021
Publisher: Springer Berlin Heidelberg
Keyword: Type 1 Diabetes
Published in: Diabetologia / Issue 4/2021
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-020-05378-z

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

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Graphical abstract

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