title: Low-dose antigen promotes induction of FOXP3 in human CD4+ T cells.
abstract: Low Ag dose promotes induction and persistence of regulatory T cells (Tregs) in mice, yet few studies have addressed the role of Ag dose in the induction of adaptive CD4(+)FOXP3(+) Tregs in humans. To this end, we examined the level of FOXP3 expression in human CD4(+)CD25(-) T cells upon activation with autologous APCs and varying doses of peptide. Ag-specific T cells expressing FOXP3 were identified by flow cytometry using MHC class II tetramer (Tmr). We found an inverse relationship between Ag dose and the frequency of FOXP3(+) cells for both foreign Ag-specific and self Ag-specific T cells. Through studies of FOXP3 locus demethylation and helios expression, we determined that variation in the frequency of Tmr(+)FOXP3(+) T cells was not due to expansion of natural Tregs, but instead, we found that induction, proliferation, and persistence of FOXP3(+) cells was similar in high- and low-dose cultures, whereas proliferation of FOXP3(-) T cells was favored in high Ag dose cultures. The frequency of FOXP3(+) cells positively correlated with suppressive function, indicative of adaptive Treg generation. The frequency of FOXP3(+) cells was maintained with IL-2, but not upon restimulation with Ag. Together, these data suggest that low Ag dose favors the transient generation of human Ag-specific adaptive Tregs over the proliferation of Ag-specific FOXP3(-) effector T cells. These adaptive Tregs could function to reduce ongoing inflammatory responses and promote low-dose tolerance in humans, especially when Ag exposure and tolerance is transient.
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
authors.forename: S Alice
authors.initials: SA
authors.lastname: Long
authors.forename: Mary
authors.initials: M
authors.lastname: Rieck
authors.forename: Megan
authors.initials: M
authors.lastname: Tatum
authors.forename: Paul L
authors.initials: PL
authors.lastname: Bollyky
authors.forename: Rebecca P
authors.initials: RP
authors.lastname: Wu
authors.forename: Isabelle
authors.initials: I
authors.lastname: Muller
authors.forename: Jhon-Chun
authors.initials: JC
authors.lastname: Ho
authors.forename: Heather G
authors.initials: HG
authors.lastname: Shilling
authors.forename: Jane H
authors.initials: JH
authors.lastname: Buckner
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000941:Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D000941:Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors