Determine how a normal microbial environment protects against autoimmune diabetes

About This Grant

SUMMARY Autoimmune type 1 diabetes (T1D) is caused by the T cell-mediated destruction of insulin producing beta (β) cells in the pancreas. The incidence of T1D is rising globally. This is thought to be linked to early life exposure to microbes, environmental pollutants, and even diet. Viral infections in mouse models of diabetes have shown both acceleration and protection of diabetes, but these differences occur at different ages and degree of insulitis. The deciding factor in whether CD4+ T cells will prime the immune system to initiate T1D is the inflammatory context of the initial peripheral antigen encounter, particularly the timing of type I interferon (IFN-I) exposure triggered by microbes. Unfortunately, the vast majority of research has utilized specific pathogen free (SPF) mouse models examining activation in the absence of IFN-I. These conditions are very different from the environment in which humans live. At UMN, we have created a ‘dirty’ mouse model or normal microbial environment (NME) to study how the immune system responds or develops in the presence of microbes and viral pathogens, a more physiological environment driven by IFN-I production. Thus, we now have a diabetes model that we can study with NME conditions. Depending on the age and duration of time in NME, our NOD mice can be completely protected from diabetes. Our goal is to understand how infections impact immunity to either trigger or protect against diabetes. A better understanding of this process could provide therapies that prevent or treat human diabetes. We will test three specific aims; 1) Determine the role of IFN-I on naïve CD4 T cell fate following TCR activation in SPF conditions, 2) Determine the mechanism(s) by which NME prevents autoimmune diabetes, and 3) Develop autoimmune diabetes therapies. Our goal is to determine the role of IFN-I during initial T cell fate decision between Teff and Tregs. We hypothesize this fate decision leads to iTregs and will focus on induction, survival or enhanced suppressive function. Finally, we will explore IFN-I therapy and engineered TCR Tregs for autoimmune therapy.