Aim: The aim of our study was to investigate the effect of lentinan on regulatory T cells (Tregs) in sepsis, especially on the generation of interleukin (IL)-10 via regulation of Erk-FoxO1 signaling. Methods: Ba1B/c mice were randomized into five groups: sham group, the group with burns plus Pseudomonas aeruginosa infection, and the groups with burns plus P. aeruginosa infection administered 40, 100, and 250 mg/kg of lentinan. The mice were sacrificed on postburn days 0, 1, 2, 3, and 4, respectively, with eight animals per group at each time point. The peripheral blood CD4(+) CD25(+) Tregs and CD4(+) T cells were isolated using magnetic microbeads. The phenotypes were analyzed by flow cytometry. The cytokine levels were determined with enzyme-linked immunosorbent assay (ELISA). Signal transduction was studied by Western blot, quantitative polymerase chain reaction (qPCR), and luciferase assay. Results: The IL-10-producing capacity of CD4(+) CD25(+) Tregs was significantly enhanced in the group with burns plus P. aeruginosa infection, compared with the sham group. Administration of lentinan significantly decreased IL -10 production and FoxP3 expression of CD4(+) CD25(+) Tregs. The proliferative activities of CD4(+) T cells, however, were restored. Lentinan decreased lipopolysaccharide (LPS)-induced IL-10 production in the Tregs isolated from burned mice. In addition, lentinan attenuated LPS-stimulated Erk-FoxO1 activation. Conclusions: Lentinan may improve the outcome of postburn sepsis by suppressing LPS-triggered Erk-FoxO1 activation. Consequently, the hyperfunction of CD4(+) CD25(+) Tregs is inhibited, leading to a shift in the inflammatory status from Th2 to Th1 in postbum sepsis. (C) 2016 Elsevier Ltd and ISBI. All rights reserved.