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

Human CD4CD25 regulatory T (TR) cells express the transcription factor forkhead box p3 (FOXP3) and have potent immunosuppres- sive properties. Although naturally occurring TR cells develop in the thymus, adaptive TR cells de- velop 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 contin- uous antigen stimulation. After 2 days of stimula- tion of CD4CD25- T cells, the cells expressed FOXP3 and COX-2 and displayed potent immuno- suppressive 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 mark- ers consistent with an activated phenotype and se- creted high levels of TGF-, IL-10, and PGE2. However, the suppressive phenotype was found ex- clusively in cells that proliferated upon activation. These data support the notion that activation of naive CD4 T cells leads to concomitant acquisi- tion of effector and suppressive properties. J. Leu- koc. Biol. 83: 000-000; 2008.