Abstract
In a murine model of repeated exposure of the skin to infective Schistosoma mansoni cercariae, events leading to the priming of CD4 cells in the skin draining lymph nodes were examined. The dermal exudate cell (DEC) population recovered from repeatedly (4x) exposed skin contained an influx of mononuclear phagocytes comprising three distinct populations according to their differential expression of F4/80 and MHC-II. As determined by gene expression analysis, all three DEC populations (F4/80-MHC-IIhigh, F4/80+MHC-IIhigh, F4/80+MHC-IIint) exhibited major up-regulation of genes associated with alternative activation. The gene encoding RELMα (hallmark of alternatively activated cells) was highly up-regulated in all three DEC populations. However, in 4x infected mice deficient in RELMα, there was no change in the extent of inflammation at the skin infection site compared to 4x infected wild-type cohorts, nor was there a difference in the abundance of different mononuclear phagocyte DEC populations. The absence of RELMα resulted in greater numbers of CD4+ cells in the skin draining lymph nodes (sdLN) of 4x infected mice, although they remained hypo-responsive. Using mice deficient for IL-4Rα, in which alternative activation is compromised, we show that after repeated schistosome infection, levels of regulatory IL-10 in the skin were reduced, accompanied by increased numbers of MHC-IIhigh cells and CD4+ T cells in the skin. There were also increased numbers of CD4+ T cells in the sdLN in the absence of IL-4Rα compared to cells from singly infected mice. Although their ability to proliferate was still compromised, increased cellularity of sdLN from 4x IL-4RαKO mice correlated with reduced expression of Fas/FasL, resulting in decreased apoptosis and cell death but increased numbers of viable CD4+ T cells. This study highlights a mechanism through which IL-4Rα may regulate the immune system through the induction of IL-10 and regulation of Fas/FasL mediated cell death.
Highlights
Schistosomiasis is a debilitating disease that develops following percutaneous infection with the parasitic helminth Schistosoma spp [1, 2]
In the skin infection site, three mononuclear phagocyte populations were identified which exhibited up-regulation of genes associated with alternative activation, in particular the gene encoding Resistin-like molecule α (RELMα)
In repeatedly infected mice deficient in RELMα, there was no change in the abundance of mononuclear phagocytes in the skin, and CD4+ cells in the skin draining lymph nodes remained hypo-responsive
Summary
Schistosomiasis is a debilitating disease that develops following percutaneous infection with the parasitic helminth Schistosoma spp [1, 2]. In order to investigate the effect of repeated infection with schistosome cercariae on the immune response, we developed an experimental model whereby mice were exposed via their pinnae once (1x), or repeatedly (4x), to doses of infective S. mansoni cercariae [4]. Repeated infections resulted in the development of CD4+ T cell hypo-responsiveness in the skin-draining lymph nodes (sdLN), as well as decreased immunopathology in the liver generated in response to eggs released by adult worms [4]. CD4+ T cells in the sdLN from 4x mice had reduced ability to proliferate and secrete cytokines in response to larval schistosome antigens, and this was shown to be IL-10 dependent [6, 8]
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