Circulating human CD4 +CD25 ++CD127 -FOXP3 + T cells with a persistent demethylated regulatory T cell (Treg)-specific demethylated region Foxp3 gene are considered natural Tregs (nTregs). We have shown that it is possible to identify functional Agreactive nTregs cells for a range of different common viral and vaccination Ags. The frequency of these Ag-reactive nTregs within the nTreg population is strikingly similar to the frequency of Ag-reactive T effector cells within the CD4 + T cell population. The Ag-reactive nTregs could be recognized with great specificity by induction of CD154 expression. These CD154 + Ag-reactive nTregs showed a memory phenotype and shared all phenotypical and functional characteristics of nTregs. The isolated CD154 + nTregs could be most efficiently expanded by specific antigenic stimulation, while their Ag-reactive suppressive activity was maintained. After an in vivo booster Ag challenge, the ratio of Ag-reactive T cells to Ag-reactive Tregs increased substantially, which could be attributed to the rise in effector T cells but not Tregs. In conclusion, the nTreg population mirrors the effector T cell population in the frequency of Ag-reactive T cells. Isolation and expansion of functional Ag-reactive nTregs is possible and of potential benefit for specific therapeutic goals. Copyright

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Journal Journal of Immunology
Litjens, N.H.R, Boer, K, & Betjes, M.G.H. (2012). Identification of circulating human antigen-reactive CD4 + FOXP3 + natural regulatory T cells. Journal of Immunology, 188(3), 1083–1090. doi:10.4049/jimmunol.1101974