The role of recirculating thymic T regulatory cells in central tolerance and immune homeostasis 3148

Abstract Description T regulatory cells (Tregs) generated during the perinatal period prevent specific types of autoimmunity related to AIRE deficiency. In contrast, Tregs from adult mice, which consist of Tregs generated throughout life fail to protect AIRE-/- mice from autoimmune disease. The mechanism that causes perinatal Tregs to differ functionally from adult Tregs is unknown. We observed that some mature Tregs recirculate back to the thymus (Recirculating Thymic Tregs/RT-Tregs) and comprise up to 50% of the thymic Treg compartment by 5 weeks of age. This coincides with a decline in AIRE+ thymic epithelial cells. We hypothesize that perinatal Tregs are functionally distinct from adult-derived Tregs due to feedback from RT-Tregs. We propose that RT-Tregs are derived from perinatal Tregs that deplete AIRE+ cells thereby altering the TCR repertoire/function of adult Tregs. To test this, we developed a mouse model that selectively labels perinatally-derived Tregs: Rag-Rox-CRE-Rox x CAGS-DRE-ERT2 x Foxp3-iDTR mice. In these mice all Tregs are labeled with GFP and DTR until tamoxifen administration-Tregs that develop afterwards are GFP/DTR-. A complementary strain that uses Rag-Rox-STOP-Rox-CRE was developed to selectively label adult-derived Tregs. These models allow us to track the proportion of perinatally-derived Tregs throughout life in all tissues and deplete them to test the role of perinatally- versus adult-derived Tregs on thymic Treg generation and preventing autoimmunity later in life. Funding Sources Supported by 5R01A1159554-02 (Development of Immune Tolerance) Topic Categories Hematopoiesis and Immune System Development (HEM)