UCSF

The developmental programs that generate a broad repertoire of regulatory T cells (T_reg cells) able to respond to both self antigens and non-self antigens remain unclear. Here we found that mature T_reg cells were generated through two distinct developmental programs involving CD25⁺ T_reg cell progenitors (CD25⁺ T_regP cells) and Foxp3^lo T_reg cell progenitors (Foxp3^lo T_regP cells). CD25⁺ T_regP cells showed higher rates of apoptosis and interacted with thymic self antigens with higher affinity than did Foxp3^lo T_regP cells, and had a T cell antigen receptor repertoire and transcriptome distinct from that of Foxp3^lo T_regP cells. The development of both CD25⁺ T_regP cells and Foxp3^lo T_regP cells was controlled by distinct signaling pathways and enhancers. Transcriptomics and histocytometric data suggested that CD25⁺ T_regP cells and Foxp3^lo T_regP cells arose by coopting negative-selection programs and positive-selection programs, respectively. T_reg cells derived from CD25⁺ T_regP cells, but not those derived from Foxp3^lo T_regP cells, prevented experimental autoimmune encephalitis. Our findings indicate that T_reg cells arise through two distinct developmental programs that are both required for a comprehensive T_reg cell repertoire capable of establishing immunotolerance.