Revisiting Development and Homeostasis of Thymic Regulatory T Cells in Type 1 Diabetes

Regulatory T cells (Tregs) seem to play a protective role in the pathogenesis of type 1 diabetes (T1D), a serious autoimmune disease. Studies using T1D murine models such as the non-obese diabetic (NOD) mouse have suggested that T1D is initiated partly due to either paucity and/or defectiveness of Tregs in the periphery, although other reports contradict this. In contrast Treg development in the thymus is thought to be normal in T1D-prone mice. However, these latter studies neglect to investigate different thymic Treg subpopulations such as precursor Tregs, newly developed Tregs and thymic resident Tregs. It is therefore important to establish a pattern of Treg populations for a better understanding of the relationship between regulatory cells and T1D. Using for the first time RAG-GFP reporter mice, this project re-investigated the Treg frequency and number in primary and secondary lymphoid organs in NOD mice in comparison to non-diabetes prone control mice. Time course flow cytometry studies revealed that there was a developmental fault in Treg generation in NOD mice; both precursor and mature Treg frequencies and numbers were increased with respect to control mice. However, further analysis of the mature Treg thymocytes demonstrated there was a paucity in newly developed Tregs compared to control mice, and concomitantly an increase in thymic resident Tregs in the NOD mice. These events were not related to intra-thymic IL-2 levels. Interestingly, B cells may have a role in Treg development and/or peripheral homeostasis in an age-dependent manner. The data presented in this project provides new evidence on the inticacies of the relationship between Tregs and T1D, and emphasize the importance of succinct analyses of distinct thymic Treg subpopulations to validate this relationship.