Amplifying peripheral tolerance in type 1 diabetes through regulatory T cells and inhibitory Fc receptors
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Type I Diabetes (TID) is a devastating autoimmune disorder in which autoreactive T cells attack the insulin-producing [beta] cells in the pancreatic islets of Langerhans and control of blood glucose levels is lost. A therapy that could target the autoreactive immune cells and prevent the destruction of the [beta] cells could circumvent the complications of exogenous insulin therapy and reduce the burden on diabetic patients. In this research, we describe an immunogenic compound, Ig--GAD1, that is able to protect against TID in a mouse model of disease. When administered to mice, Ig--GAD1 binds to Fc[gamma]RIIB on CD8--CD4--CD11c+ Dendritic Cells (DC), which then produce IL--10 and expand Regulatory T cells (Tregs). Tregs in our model of diabetes are actually comprised of two types: FoxP3hi and FoxP3int, named for their level of expression of the canonical FoxP3 transcription factor. When IL--10 is produced, Tregs are expanded and the FoxP3int population, which highly expresses the suppressive protein TGF[beta], traffics to the pancreas using CD62L and protects against TID. Intriguingly, this FoxP3int population also expresses ROR[gamma]t, the canonical transcription factor for Th17 pathogenic cells. This implies that transitional T cells are not only plastic, as has been described, but functional. Mice treated with Ig--GAD1 at a very early age were protected from TID through week 26 through this mechanism, highlighting the effectiveness of therapies targeted against the autoreactive immune system.
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