Humanized in vivo Model for Autoimmune Diabetes
Abstract
In this study we investigated the tolerance mechanisms of high and low avidity T cells reactive to the diabetes autoantigen glutamic acid decarboxylase 65 (GAD65) and their potential role in type 1 diabetes pathogenesis. In diabetes-associated DR4 HLA humanized mice, transgenically expressing GAD65-reactive human T cells, we found that high avidity, but not low avidity, T cells can migrate to the islets and mediate a loss in pancreatic islet function. Interestingly, low avidity GAD65 T cells generate the suppressive cytokine IL-10 and have a naive phenotype in contrast with the phenotype of high avidity T cells, which make only IFN and are activated in the periphery. While both T cell receptors undergo deletional central tolerance, peripheral tolerance in high avidity T cells occurs through activation-induced cell death (AICD). In low avidity T cells it may occur through the generation of IL-10-producing Tr1 cells. These findings suggest that, within a single antigen-specific polyclonal T cell pool, both high avidity islet-infiltrating cells and potentially regulatory T cells may coexist and that antigen-specific T cells targeting the whole pool may have negative consequences.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 07, 2010
- Accession Number
- ADA540948
Entities
People
- Gerald T. Nepom
Organizations
- Benaroya Research Institute