In vivo activation of CD8+ cells with high Ag dose stimulates proliferation but not lytic effector function. (A) C57BL/6 mice received OT-I/PL LN cells by adopt
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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 ...
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