Poster Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

  The serine protease granzyme A controls activation of innate immunity and type 1 interferon production in non-obese diabetic mice (#168)

Zia Mollah 1 , Hong S Quah 1 , Jonathan Chee 1 , Gaurang Jhala 1 , Prerak Trivedi 1 , Balasubramanian Krishnamurthy 1 , Kate Graham 1 , Stacey Fynch 1 , Joseph Trapani 2 , Thomas Brodnicki 1 , Thomas Kay 1 , Helen Thomas 1
  1. St. Vincents Institute, Fitzroy, Melbourne, VIC, Australia
  2. Peter MacCallum Cancer Centre, East Melbourne, Australia, VIC, Australia
Sensing of nucleic acids by innate immune pathways is essential for normal immunity against viruses, and defects in this process lead to autoimmune diseases such as type 1 diabetes. Cleavage of intracellular DNA is mediated by molecules of the SET complex, and this complex can be activated by the serine protease granzyme A. Mutations in molecules in the SET complex, such as the 3’ endonuclease Trex1, result in autoimmunity in mice and man that is driven by excessive production of type 1 IFN. While studying cytotoxic T cell-mediated b cell death in type 1 diabetes, we discovered that non-obese diabetic (NOD) mice lacking granzyme A have accelerated diabetes. Granzyme A-deficient NOD mice had more islet autoantigen-specific T cells in the thymus, pancreatic lymph node and islets when compared to wild-type NOD mice. Islets from granzyme A-deficient NOD mice had a 6-fold increase in islet expression of IFN-regulated genes including Mx1, Ifit1, Isg15 and Oas1a between 2-6 weeks of age, suggesting excessive activation of innate immunity and type 1 IFN production. Bone marrow chimera experiments indicate that loss of granzyme A expression in non-haematopoietic cells is important for disease acceleration. Our data indicate a crucial role for granzyme A in controlling activation of innate immunity, and if left unchecked in a genetic background that is prone to autoimmunity, disease develops.