Schistosomiasis mansoni, a tropical helminthic disease, is caused by disseminated worm eggs that induce CD4(+) T-cell mediated granulomatous inflammation and fibrosis. T suppressor cell activity has been proposed as one of the mechanisms active in the down-modulation of the murine disease during the chronic stage (16-20 weeks of the infection). In recent years a new category of the CD4(+) CD25(+) T regulatory (Treg) lymphocyte has been identified that maintains immune tolerance to self, and also functions in the regulation of parasite-induced immunopathology. The Foxp3 gene which encodes the transcription factor Scurfin was found to be expressed by and required for the generation of CD4(+) CD25(+) T reg. At 8 weeks of the infection Foxp3 gene expression of splenocytes was similar to that of naive mice, but increased fourfold by 16 weeks. In contrast, granulomatous livers at 8 and 16 weeks showed 10- and 30-fold increases, respectively, in gene expression compared with normal liver. The percentage of granuloma CD4(+) CD25(+) T cells rose from 12% at 8 weeks to 88% at 16 weeks of the infection. Foxp3 expression was 3.5-fold higher in the CD4(+) CD25(+) versus the CD4(+) CD25(-) T cells in the 8 week infection granulomas. As a novel observation neuropilin-1 membrane expression, a recently identified marker for Treg, was correlated with Foxp3 expression in the granuloma CD4(+) CD25(+) but not the CD25(-) cells. Co-incubation with polyclonal stimulation of CD4(+) CD25(+) splenic cells with CD4(+) CD25(-) cells suppressed proliferation of the latter. Retroviral transfer of the Foxp3 gene at the onset of granuloma formation enhanced fourfold Foxp3 expression in the granuloma CD4(+) CD25(+) T cells and strongly suppressed full granuloma development. Gene transfer also significantly enhanced transforming growth factor-beta, interferon-gamma and interleukin-4 but not interleukin-10 expression. It is concluded, that CD4(+) CD25(+), Foxp3(+) Treg cells also regulate schistosome egg-induced immunopathology.