Although the initial events contributing to the development of Type 1 Diabetes (T1D) remain elusive, mounting evidence supports a crucial role for the innate immune system and environmental factors, such as viruses, in the progression of disease. Further investigation is needed to understand how innate immune activation leads to loss of immunological tolerance and ensuing beta cell destruction by the CD8+ T cell. Therefore, the long- term goal of this research is to understand the causal relationship between genetic susceptibility, precipitating environmental factors, and innate immune mediators in the initiation and progression of T1D. This particular application aims to assess the effect of Type 1 Interferons (T1-IFN) on beta cell and CD8+ T cell interactions in a human in vitro model of T1D. Previous studies have shown that T1-IFN are found in the islets of T1D patients along with increased MHC Class I (MHC-I) expression. However, the underlying molecular mechanisms leading to increased MHC-I within the beta cell have not been well characterized. Also, due to the immunomodulatory effects displayed by T1-IFN, the presence of these cytokines within the diabetic islet may serve to modulate CD8+ T cell responses. The central hypothesis portends that T1-IFN alter the microenvironment of the diabetic islet through regulation of members of the MHC-I antigen processing and presentation pathway and by directly enhancing CTL-mediated beta cell death. This hypothesis will be tested through two specific aims: 1) Determine how T1-IFN regulate MHC-I antigen processing & presentation by beta cells; and 2) Elucidate the impact of T1-IFN on beta cell recognition and destruction by autoreactive CD8+ T cells.
In Aim 1, utilizing beta cell lines and primary human islets, mechanistic studies aimed at characterizing the antigen processing and presentation pathway, specifically the immunoproteasome, will be performed. This will be followed by in depth analysis of signaling pathways responsible for inducing these responses in beta cells. Expounding upon preliminary studies, aim 2 will investigate the immunomodulatory effects of T1-IFN in the context of CD8+ T cell cytotoxicity, specifically factors involved in the granule exocytosis pathway and TNF receptor ligand family. Furthermore, T1-IFN mediated signaling pathways important for the acquisition of CD8+ T cell effector function will be analyzed. A majority of the current knowledge regarding T1-IFN biology has been derived using other disease models. This research is innovative in that it seeks to understand existing paradigms in T1-IFN biology in the context of T1D autoimmunity. This research is significant because successful completion of these studies will provide direct evidence as to how T1-IFN modulate beta cell - CD8 T cell interactions and will provide a mechanistic link between environmental factors, immune activation, and T1D pathogenesis. Ultimately, the knowledge gained here will serve as a foundation for future studies examining the functional significance of T1D susceptibility alleles in T1-IFN responsiveness, which may lead to the development of new therapeutic approaches in T1D that specifically target the T1-IFN signaling pathway.
Type 1 Diabetes (T1D) is characterized by the autoimmune destruction of insulin producing cells resulting in lifelong therapy for patients and a significant financial burden on our healthcare system. With the incidence of T1D steadily climbing, a preponderance of evidence points to the environment, particularly viruses, in T1D progression. Therefore, the goal of the proposed research is to further understand how the activation of the immune system in response to environmental cues contributes to initiation and progression of T1D.
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