Recent evidence has revealed an unsuspected suppressive role played by neutrophils during microbial infections. An especially intriguing aspect of this role is the ability of neutrophils to produce interleukin (IL)-10 following interaction with lipopolysaccharide (LPS)-stimulated regulatory T (Treg) cells. The present study demonstrates that generation of IL-10 in neutrophils induced by LPS-stimulated Treg cells required direct cell-cell contact. This effect was dependent on the binding of CD11b and intercellular adhesion molecule 1. Neither stimulation of neutrophils with LPS nor their culture with unstimulated Treg cells, CD3/CD28 monoclonal antibodies-stimulated Treg cells, or T conventional cells affected intracellular IL-10 expression. IL-10-positive neutrophils were also induced by exogenous IL-10, providing an example of a positive feedback loop. Both LPS-stimulated Treg cells and exogenous IL-10 exclusively promoted posttranslational modifications of histones, H3K4me3 and H3Ac Lys4, that activate IL-10 genomic locus in neutrophils, while the promoter of IL-10 gene was inactive in resting, LPS-stimulated neutrophils, following blocking of direct interaction with LPS-stimulated Treg cells or in LPS-preactivated neutrophils incubated with LPS-stimulated Treg cells. We additionally confirmed the presence of IL-10-producing neutrophils in vivo in patients with periodontal abscess induced by Gram-negative bacteria, as opposed to neutrophils isolated from the site of aseptic inflammation in patients with neuromyelitis optica.