title: Identification of circulating human antigen-reactive CD4+ FOXP3+ natural regulatory T cells.
abstract: 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 Ag-reactive 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.
authors.affiliation: Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
authors.forename: Nicolle H R
authors.initials: NH
authors.lastname: Litjens
authors.forename: Karin
authors.initials: K
authors.lastname: Boer
authors.forename: Michiel G H
authors.initials: MG
authors.lastname: Betjes
mesh_terms: D000941:Antigens / Q000276:immunology; D001773:Blood Cells / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D023201:CD40 Ligand; D002469:Cell Separation; D003584:Cytological Techniques; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000941:Antigens; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D023201:CD40 Ligand