Thymic regulatory T cells arise via two distinct developmental programs.

Abstract

The developmental programs that generate a broad repertoire of regulatory T cells (Treg cells) able to respond to both self antigens and non–self antigens remain unclear. Here we found that mature Treg cells were generated through two distinct developmental programs involving CD25+ Treg cell progenitors (CD25+ TregP) and Foxp3lo Treg cell progenitors (Foxp3lo TregP). The CD25+ TregP had higher rates of apoptosis and interacted with thymic self-antigens with higher affinity than Foxp3lo TregP, and had a T cell antigen receptor (TCR) repertoire and transcriptome distinct from that of Foxp3lo TregP. The development of CD25+ TregP and Foxp3lo TregP was controlled by distinct signaling pathways and enhancers. Transcriptomic and histocytometric data suggested that CD25+ TregP and Foxp3lo TregP arose by coopting negative and positive selection programs, respectively. Treg cells derived from CD25+ TregP, but not Foxp3lo TregP, prevented experimental autoimmune encephalitis. Our findings indicate that Treg cells arise through two distinct developmental programs that are both required for a comprehensive Treg cell repertoire capable of establishing immune tolerance.