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Retroviral Foxp3 gene transfer ameliorates liver granuloma pathology in Schistosoma mansoni infected mice
Author(s) -
Singh Kameshwar P.,
Gerard Herve C.,
Hudson Alan P.,
Reddy Thipparthi R.,
Boros Dov L.
Publication year - 2005
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/j.1365-2567.2004.02083.x
Subject(s) - il 2 receptor , foxp3 , biology , immunology , granuloma , immune system , schistosoma mansoni , microbiology and biotechnology , t cell , schistosomiasis , helminths
Summary 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 naïve 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‐β, interferon‐γ and interleukin‐4 but not interleukin‐10 expression. It is concluded, that CD4 + CD25 + , Foxp3 + Treg cells also regulate schistosome egg‐induced immunopathology.