Little is known about how T cell pathogenesis is modulated in the islets during T1D, yet this is a critical obstacle for preventing destruction of remaining islets or beta cell grafts. Therefore, we must elucidate mechanisms that promote and prevent the pathogenic autoimmune response in the islets. Our data in the NOD mouse model show that different populations of CD11c mononuclear phagocytes have countervailing roles in restimulating or inducing tolerance in islet-infiltrating T cells as islet infiltration progresses. While macrophages have been identified in human pancreatic islets, these likely represent a complex assortment of several mononuclear phagocytic cell populations that play a role in islet destruction. As a result, our goal is to identify the populations of mononuclear phagocytes within the islets of normal, autoantibody positive, and type 1 diabetes subjects.
ADDENDUM: Type 1 diabetes (T1D) lacks therapeutic approaches that stop the autoimmune destruction of the beta cells. T cells may be the major mediator of destruction in T1D, but they do not act alone. T cells are influenced by myeloid cells in the islets. Our preliminary data show that human islets contain multiple populations of myeloid cells with some populations that are only present in the islets of T1D patients. As a key regulator of T cells in T1D, the islet myeloid cells are a potential target for therapeutic intervention for T1D. However, human islet myeloid cells are severely understudied. Thus, before we can develop myeloid therapies for T1D, we must understand the human islet myeloid populations and identify specific molecules on the myeloid cells for therapeutic targeting. Our goals are to identify the myeloid cell populations in the islets of non-diabetic, autoantibody positive, and type 1 diabetic donors. We will determine where these populations are localized in the islets, as well as how these populations correlate with islet health and interact with T cells in the islets. These analyses will create a picture of the myeloid landscape of human islets and begin to elucidate the roles of human myeloid populations in normal and type 1 diabetic islets. Because myeloid cells are present in all islets, the knowledge gained will be relevant to understanding how these cell populations function in T1D and T2D.