The importance of regulatory T-cell heterogeneity in maintaining self-tolerance.

CD4(+) Forkhead box protein 3 (Foxp3)(+) regulatory T cells (Tregs) are the major cell type that mediates dominant tolerance in the periphery. Over the past decade, extensive study of Tregs has revealed that these cells express substantial heterogeneity to maintain tolerance and regulate immune responses. Tregs possess heterogeneity with respect to their origin and processes for development, functional activity, migratory pattern, and activation status. Some of the same environmental cues and molecular pathways utilized to generate specialized T-effector cells are also integrated by Tregs to colocalize and fine-tune suppressive mechanisms to optimally regulate and restrain distinctive self and antigen-specific T-cell responses. Here, we review our current understanding and significance of Treg heterogeneity in maintaining peripheral immune tolerance. We also highlight recent work from our laboratory that has studied the extent phenotypically distinct Treg subsets are related to each other and expand in an ordered fashion to give rise to highly activated short-lived Klrg1(+) suppressor cells to optimize immune regulation and maintain homeostasis of the Treg compartment.