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Differentiation of naive CD4+ T cells into CD4+CD25+FOXP3+ regulatory T cells by continuous antigen stimulation

Human CD4+CD25+ regulatory T (TR) cells express the transcription factor forkhead box p3 (FOXP3) and have potent immunosuppressive properties. While naturally occurring TR cells develop in the thymus, adaptive TR cells develop in the periphery from naive CD4+ T cells. Adaptive TR cells may express cyclooxygenase type 2 (COX‐2) and suppress effector T cells by a PGE2‐dependent mechanism, which is reversible with COX inhibitors. In this study we have characterized the differentiation of naive CD4+ T cells into adaptive TR cells in detail during 7 days of continuous antigen stimulation. After 2 days of stimulation of CD4+CD25– T cells, the cells expressed FOXP3 and COX‐2 and displayed potent immunosuppressive properties. The suppressive phenotype was present at all observed time‐points from Day 2, although suppression was merely present at Day 7. The adaptive TR cells expressed cell surface markers consistent with an activated phenotype and secreted high levels of TGF‐β, IL‐10, and PGE2. However, the suppressive phenotype was found exclusively in cells that proliferated upon activation. These data support the notion that activation of naive CD4+ T cells leads to concomitant acquisition of effector and suppressive properties.