Type 1 diabetes develops over many years and is characterized ultimately by the destruction of insulin-producing pancreatic beta cells by autoreactive T cells. Nonetheless, the role of innate cells in the initiation of this disease remains poorly understood. Here, we show that in young female nonobese diabetic mice, physiological beta cell death induces the recruitment and activation of B-1a cells, neutrophils and plasmacytoid dendritic cells (pDCs) to the pancreas. Activated B-1a cells secrete IgGs specific for double-stranded DNA. IgGs activate neutrophils to release DNA-binding cathelicidin-related antimicrobial peptide (CRAMP), which binds self DNA. Then, self DNA, DNA-specific IgG and CRAMP peptide activate pDCs through the Toll-like receptor 9-myeloid differentiation factor 88 pathway, leading to interferon-α production in pancreatic islets. We further demonstrate through the use of depleting treatments that B-1a cells, neutrophils and IFN-α-producing pDCs are required for the initiation of the diabetogenic T cell response and type 1 diabetes development. These findings reveal that an innate immune cell crosstalk takes place in the pancreas of young NOD mice and leads to the initiation of T1D.

The development of type 1 diabetes involves a complex interaction between pancreatic beta-cells and cells of both the innate and adaptive immune systems. Analyses of the interactions between natural killer (NK) cells, NKT cells, different dendritic cell populations and T cells have highlighted how these different cell populations can influence the onset of autoimmunity. There is evidence that infection can have either a potentiating or inhibitory role in the development of type 1 diabetes. Interactions between pathogens and cells of the innate immune system, and how this can influence whether T cell activation or tolerance occurs, have been under close scrutiny in recent years. This Review focuses on the nature of this crosstalk between the innate and the adaptive immune responses and how pathogens influence the process.