Retroviral Foxp3 gene transfer ameliorates liver granuloma pathology in Schistosoma mansoni infected mice.
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.
Singh
Kameshwar P
KP
Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Gerard
Herve C
HC
Hudson
Alan P
AP
Reddy
Thipparthi R
TR
Boros
Dov L
DL
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006099:Granuloma / Q000276:immunology / Q000469:parasitology / Q000628:therapy*; D008109:Liver Diseases, Parasitic / Q000276:immunology / Q000469:parasitology / Q000628:therapy*; D051379:Mice; D008808:Mice, Inbred CBA; D015375:Receptors, Interleukin-2 / Q000032:analysis; D012190:Retroviridae / Q000235:genetics; D012555:Schistosomiasis mansoni / Q000276:immunology / Q000628:therapy*; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology
D016207:Cytokines; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015375:Receptors, Interleukin-2
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