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.