The focus of our research project is to improve the understanding of how antigenic stimulation of the B lymphocyte repertoire development during early life may protect from Type 1 Diabetes (T1D). Specifically, we are investigating how exposure to the common pathogen Group A Streptococcus promotes the formation of a T1D-suppressive natural antibody repertoire. Exposure to microorganism associated antigens during early life can protect diabetes-prone mice from developing T1D, and epidemiological studies in humans as well as studies in diabetes prone mice and rats have reported that that immune responses to Group A Streptococcus (GAS) are associated with protection from T1D. In humans and mice, infection or immunization with GAS results in a robust B cell response and the production of antibodies reactive with GAS cell wall-polysaccharide-associated N-acetyl-D- glucosamine (GlcNAc) epitopes, yet the role of these responses in protection from T1D has not been previously examined. We have shown that GlcNAc-reactive antibodies, produced following exposure to GAS cell wall antigens, bind GlcNAc-modified beta cell antigens. GlcNAc-reactive B cells elicited during neonatal immune responses to GAS traffic to the pancreas during T1D in non-obese diabetic (NOD) mice, and transfer protection upon adoptive transfer into naïve recipients. GlcNAc-reactive natural antibodies produced by these cells opsonize damage-associated molecular patterns on stressed beta cells and promotes clearance of their diabetogenic antigens, thereby attenuating the pathogenesis of T1D. Our goal is to evaluate the role of GlcNAc-reactive B lymphocyte development and antibody production in T1D in humans to identify novel biomarkers for improved prediction of T1D susceptibility, and the development of vaccination or probiotic strategies aimed at boosting natural antibody-mediated suppression of T1D progression.