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. 2005 Mar;114(3):410-7.
doi: 10.1111/j.1365-2567.2004.02083.x.

Retroviral Foxp3 gene transfer ameliorates liver granuloma pathology in Schistosoma mansoni infected mice

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Retroviral Foxp3 gene transfer ameliorates liver granuloma pathology in Schistosoma mansoni infected mice

Kameshwar P Singh et al. Immunology. 2005 Mar.

Abstract

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.

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Figures

Figure 1
Figure 1
Relative Foxp3 gene expression in the spleens and granulomatous livers of Schistosoma mansoni infected mice. Real-time RT–PCR assay was performed for the spleens (a) and livers (b) of normal, uninfected mice and those at 8 and 16 weeks after infection. Calculation of relative levels is described in Materials and Methods. Data presented as means ± SE of six to eight mice in each group. Statistically significant differences were observed when compared with control naïve group: *, P < 0·001; †, P < 0·0001.
Figure 2
Figure 2
Relative Foxp3 gene expression in the subset of CD4+ cells in the liver granulomas from 8 weeks infected mice. Foxp3 transcript levels of CD4+ CD25+ cells were calculated as fold increase over the mean values of the CD4+ CD25−. The mean values of the latter were normalized to 1 and the relative increase was calculated by dividing the CD25+ value by the CD25− value. Real-time RT–PCR assay was performed in the (a) CD4+ CD25− and CD4+ CD25+ and (b) CD25+ NP− and CD25+ NP+ subsets of CD4+ and CD4+ CD25+ cells. Data presented as means ± SE of six to eight mice. Statistically significant differences were observed when CD4+CD25− were compared with CD4+ CD25+ and CD25+ NP− with CD25+ NP+ cells: *, P < 0·05; †, P < 0·01.
Figure 3
Figure 3
Proliferative response of CD4+, CD4+ CD25+ and CD4+ CD25− cells isolated from spleens of naïve, 8 and 16 weeks infected mice. Proliferation assays were performed by stimulating the cells with plate bound anti-CD3 and anti-CD28 in culture for 72 hr. Data presented as means ± SE of six to eight mice in each group. Experiments were repeated twice. Statistically significant difference observed when compared with their respective group subsets of CD4+ cells: *, P < 0·05; †, P < 0·01; ‡, P < 0·001 and §, P < 0·0001.
Figure 4
Figure 4
Relative Foxp3 (a) and cytokine genes (TGF-β, b, IL-10, c, IFN-γ, d, IL-4, e) expression in granuloma CD4+ CD24− and CD4+ CD25+ cells following retroviral gene transfer of Foxp3 in 8 weeks infected mice. In (a–d) the mean values of VGCD25− cells and VGCD25+ cells (derived from control MIGR1 vector recipient mice) were normalized to 1 and the relative increase shown by FGCD25+ cells (derived from Foxp3 gene recipient mice) was calculated as in Fig. 2. Real time RT–PCR assays were performed in cells from MIGR1 vector or Foxp3 gene transferred mice. Data presented as means ± SE of five mice in each group. Experiment was repeated twice. Statistically significant differences were observed when compared with MIGR1 vector alone group: *, P < 0·05; †, P < 0·001 and ‡, P < 0·0001.

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