Development of a Commensal Microbiota Molecular Mimicry Model

About This Grant

PROJECT SUMMARY The gastrointestinal tract is colonized by a complex community of commensal bacteria living in harmony with the host. It is now well known that the composition of this microbiome and its interaction with the immune system can have a profound impact on health and disease, not only in the gut environment but throughout the whole body. As such, microbial dysbiosis in the gut is linked to not only inflammatory bowel diseases (IBD), but also several types of autoimmunity, metabolic diseases, and cancer. Indeed, many autoimmune diseases are associated with the prevalence of particular commensal taxa, suggesting a causative link between immune responses against the microbiota and autoantigens. This idea, known as the mucosal origins hypothesis, involves the concept of immune epitope spreading where adaptive immune responses spread from foreign antigens in microbiota to autoantigens in the joints (in the case of rheumatoid arthritis) or other tissues. Epitope spreading may be facilitated by similarities in T cell and B cell epitopes expressed by the two entities, a concept known as molecular mimicry. While there has been much evidence for molecular mimicry and epitope spreading during the etiology and progression of autoimmune diseases, very little is known about the mechanisms contributing to it, largely due to the absence of suitable experimental systems to carry out detailed mechanistic studies. A better understanding of the fundamental biology underlying epitope spreading from commensal bacteria to autoantigens would greatly promote our understanding of autoimmune disease development and promote future therapies. The overall goal of this project is to develop a robust in vivo model of molecular mimicry between T cell antigens of intestinal commensal microbiota and host tissues to enable detailed studies of T cell epitope spreading during the development of autoimmunity. We hypothesize that the transgenic expression of identical or similar model T cell antigens in commensal bacteria and mouse tissues coupled with the use of peptide:MHC tetramer reagents in SKG autoimmune mice will provide a very powerful experimental system for studying the development of crossreactive T cell responses to these antigens. We will establish this powerful and important tool for the field by 1) generating commensal bacteria expressing model self antigens, 2) validating T cell recognition of model antigens in mice colonized with these transgenic bacteria, and 3) tracking T cell responses to shared model antigens during the development of autoimmunity in SKG mice.