It is clear that infections can lead to dysregulation of the immune system resulting in autoimmune disease; however, the mechanisms behind this process are not well understood. CD4 T cells play integral roles both in orchestrating responses to viral pathogens as well as mediating pathology in autoimmune disease. Pathogenic CD4 anti-self responses are normally prevented by mechanisms of peripheral tolerance. Although much has been learned about the regulatory molecules that contribute to tolerance, relatively little is known about the regulation of CD4 responses to viruses. This proposal focuses on using a reductionist approach to study the roles of regulatory molecules in controlling CD4 responses to viruses while simultaneously maintaining self tolerance when the elicited anti-viral response can be deleterious to the host. The two related components of this project are: 1. ) to define the molecular control of CD4 responses to model viruses, focusing on initiation and regulation, and 2.) to examine the interplay between viruses, self-antigens, and T cell regulatory pathways in the development of autoimmunity. An autoimmune diabetes model will be used in which the infecting virus, the host response, and the presence or absence of cross-reactive self antigen can be independently controlled. This will be accomplished by expressing a defined antigen, ovalbumin (OVA), in viruses, as well as pancreatic islets, to study how pathogens can trigger OVA-targeted diabetes in recipients of OVA-specific normal T cells or T cells that lack specific control mechanisms. By engineering viruses that have differing properties with respect to persistence of infection, presence of self-antigen, and ability to elicit organ-specific inflammation, insight will be gained into the contributions of molecular mimicry and bystander activation in breaking tolerance. Understanding the role of these mechanisms, as well as the contribution of regulatory molecules, in the breakdown of tolerance has important implications for both treating and preventing autoimmune disease. Basic knowledge of CD4 responses to viruses may aid in vaccine development, drug design and a better understanding of infectious complications of immunosuppression that accompanies organ transplantation. [unreadable] [unreadable]