Alternatively Activated Mononuclear Phagocytes from the Skin Site of Infection and the Impact of IL-4Rα Signalling on CD4+T Cell Survival in Draining Lymph Nodes after Repeated Exposure to Schistosoma mansoni Cercariae

• Published in: PLoS neglected tropical diseases 2016-08, Vol.10 (8), p.e0004911-e0004911
• Main Authors: Prendergast, Catriona T, Sanin, David E, Mountford, Adrian P
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biology and Life Sciences; CD4-Positive T-Lymphocytes - immunology; Cell Survival; Cercaria - immunology; fas Receptor - genetics; Genes, MHC Class II - immunology; Intercellular Signaling Peptides and Proteins - deficiency; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - immunology; Interleukin-10 - immunology; Lymph Nodes - immunology; Lymph Nodes - parasitology; Macrophage Activation; Macrophages - immunology; Macrophages - parasitology; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Phagocytes; Receptors, Cell Surface - immunology; Receptors, Cell Surface - metabolism; Schistosoma mansoni - immunology; Schistosomiasis mansoni - immunology; Signal Transduction; Skin - cytology; Skin - immunology; Skin - parasitology; Up-Regulation
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0004911

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.