Abstract

Type 1 diabetes mellitus (T1DM) is an organ specific autoimmune disease characterized by progressive destruction of insulin-secreting pancreatic beta cells. Both T cell mediated adaptive responses, as well as innate immune processes are involved in pathogenesis. Interleukin-1 receptor associated kinase M (IRAK-M) can effectively inhibit the MyD88 downstream signals in TLR pathways, while lack of IRAK-M is known to be associated with autoimmunity. Our study showed that IRAK-M deficient (IRAK-M^-/-) non obese diabetic (NOD) mice displayed early onset and rapid progression of T1DM with impaired glucose tolerance, more severe insulitis and increased serum anti-insulin auto-antibodies. Mechanistic studies showed that enhanced activation and antigen presenting function of IRAK-M deficient antigen presenting cells (APCs) from IRAK-M^-/- mice were responsible for rapid progression of disease. Moreover, IRAK-M^-/- dendritic cells (DCs) induced enhanced activation of diabetogenic T cells in vitro and rapid onset of T1DM in vivo in immunodeficient NOD mice when co-transferred with diabetogenic T cells. This study illustrates how modulation of innate immune pathways through IRAK-M influences the development of autoimmune diabetes.