Origin and functions of pro-inflammatory cytokine producing Foxp3+ regulatory T cells

•Tregs are not just committed to suppression, but also make effector cytokines.•Pro-inflammatory cytokine+ Tregs are associated with inflammatory diseases.•Effector cytokine+ Tregs correlate with impairment of their suppressive functions.•They appear to be effector specific specialized suppressive cells in some diseases.•Effector cytokine production in Tregs is attributed to the inflammatory milieu.

CD4+CD25+Foxp3+ regulatory cells (Tregs) are a special lineage of cells central in the maintenance of immune homeostasis, and are targeted for human immunotherapy. They are conventionally associated with the production of classical anti-inflammatory cytokines such as IL-10, TGF-β and IL-35, consistent to their anti-inflammatory functions. However, emerging evidence show that they also express effector cytokines such as IFN-γ and IL-17A under inflammatory conditions. While some studies reveal that these pro-inflammatory cytokine producing Foxp3+ regulatory cells retain their suppressive ability, others believe that these cells are dys-regulated and are associated with perpetuation of immunopathology. Therefore the development of these cells may challenge the efficacy of human Treg therapy. Mechanistically, toll-like receptor (TLR) ligands and the pro-inflammatory cytokine milieu h