CD4+CD25+ regulatory T cells (Treg) Treg have tremendous potential as a novel cellular therapy for the prevention and/or treatment of autoimmune disorders such as T1D. Their phenotypic and functional diversity and the widespread distribution of these cells suggests that different Treg populations have unique roles in maintaining normal lymphocyte homeostasis in different tissues, which have not been precisely defined. The objectives of this study are to (i) examine the homing receptor expression and tissue distribution of Treg specific for a defined islet antigen in a mouse model of type 1 diabetes (T1D); (ii) determine if altering Treg localization in this model adversely effects their functional ability to prevent diabetes; (iii) compare the ability of different antigen-specific Treg subsets to prevent the initiation and/or progression of T1D; (iv) determine if antigen recognition in the secondary lymphoid tissues triggers phenotypic and functional differentiation of Treg, targeting them to sites of self-antigen expression; and (v) determine if ectopic expression of the Treg master regulator FoxP3 in different populations of islet antigen-specific effector T cells alters their localization and coverts them into therapeutically beneficial Treg. In these experiments, we will use a transgenic model of diabetes and Treg function recently described by the laboratory of Abul Abbas. In this model, DO 11.10 T cell receptor transgenic mice specific for ovalbumin (OVA) are crossed with transgenic mice that express OVA in the pancreas under control of the rat insulin promoter (RIP-OVA mice). In these animals, approximately 50% of the OVA-specific T cells are CD25+ Treg that can prevent diabetes upon co-transfer with diabetogenic OVA-specific effector T cells into RIP-OVA mice. Thus, this is an ideal experimental system in which to study phenotypically diverse Treg specific for a defined islet antigen, and characterize how their function is dependent on their homing properties and localization.
