In both humans and NOD mice type 1 diabetes (T1D) results from interactions between multiple susceptibility (Idd) genes that elicit T cell mediated autoimmune destruction of insulin producing pancreatic fi cells. We have found that in NOD mice interactions between Idd genes both within and outside the H297 MHC haplotype engender defects in hematopoietically derived antigen presenting cells (ARC) which contribute to the generation and activation of diabetogenic T cells. Our overall goal is to determine the identity and function of genes contributing to diabetogenic ARC dysfunctions in NOD mice. ARC subsets include B-lymphocytes, macrophages, and dendritic cells (DC). These ARC subsets contribute to T1D development in NOD mice at different levels of T cell development and activation. NOD macrophages and DC do not mature normally which appears to contribute to this strain's impaired ability to delete or inactivate autoreactive T cells either during their development in the thymus or in the periphery. Our data indicate impaired DC differentiation in NOD mice is in turn linked to defects in natural killer T (NKT) cells that also characterize this strain. NKT cell activation with the superagonist a- galactosylceramide inhibits T1D development in NOD mice, and our data suggests this results from the downstream maturation of DC which accumulate in the pancreatic lymph nodes (PLN) where they block pathogenic T cell responses through unknown mechanisms. Our first specific aim is to determine the mechanisms by which NKT cell activation overrides DC maturation defects in NOD mice, and how this subsequently inhibits T1D. Due to their unique ability to take up & cell antigens through specific plasma membrane bound immunoglobulin (Ig) molecules, B-lymphocytes serve as the ARC subtype which most efficiently activates diabetogenic CD4 T cell responses in NOD mice. We have found NOD mice are characterized by defects in processes that normally delete or anergize B-lymphocytes expressing autoreactive Ig molecules, but it remains unknown if this represents an Idd gene controlled dysfunction. Hence, aim 2 is to map the genes contributing to B-lymphocyte tolerance induction defects in NOD mice in order to ultimately determine their identity.
Our third aim i s to then mechanistically characterize the genes contributing to B-lymphocyte tolerance induction defects in NOD mice. Despite the availability of insulin treatment, the complications of T1D can still too often have lethal effects. Successful completion of our proposed studies might ultimately provide means for preventing the development of this devastating disease.
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