Immune responses to pathogens and vaccination can be varied with some individuals inducing optimal responses while others do not. The host genetic profile, environment and previous microbial experience could influence an individual’s response, but the relative contribution, and interactions of these different factors remains largely unknown. Here, using various multi-omics, ecological and single cell approaches, we show that release of genetic inbred strains of mice, 129-SL, PWK and C57/B6 mice, to a rewilded environment and exposure of these rewilded and laboratory specific pathogen free control mice to a helminth parasite, Trichuris muris allowed us to assess the contribution and interaction of host genotype and environment to the immune cell landscape in the blood and secondary lymphoid organs. Critically, we find that the environment has the greatest effect on circulating blood immune cells while the genetic profile has the greatest effect on the mesenteric lymph node. We also observed significant interactions between the host genetic profile, environment, and infection status in their contribution to immune cell composition, with most of the effect driven by the cells of the adaptive immune system. These findings provide a model for contribution and interactions between genetics, environment, and helminth infection in the inter-individual variation of immune responses.
Type 2 inflammation is required for expulsion of intestinal helminth parasites and is characterized by immune cell activation, type 2 cytokine production, and increased mucin production by epithelial goblet cells. Previous studies show that the prostaglandin D2 (PGD2) receptor chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) promotes type 2 inflammation in the lung via effects on immune cells, but how CRTH2 influences helminth-induced type 2 inflammation in the intestine was unclear. Here we show that CRTH2-deficient mice cleared infection with the mouse-adapted helminth parasite Nippostrongylus brasiliensis more efficiently and had increased numbers of mucin-producing goblet cells in the small intestine post-infection compared to wild type mice, despite similar levels of worm establishment. These data suggest that CRTH2 restrains goblet cell responses during intestinal helminth infection, in contrast to its pro-inflammatory role in the lung. Consistent with this idea, bone marrow-chimeric mice in which only non-hematopoietic cells lacked CRTH2 also cleared parasites more efficiently than chimeric wild type mice and had increased numbers of small intestinal goblet cells. In addition, murine small intestinal organoids that were stimulated with type 2 cytokines downregulated expression of goblet cell-associated genes following culture with PGD2. Taken together, these data suggest that the PGD2-CRTH2 pathway suppresses epithelial goblet cell responses following helminth-induced type 2 inflammation in the intestine. These findings may inform the development and use of drugs that inhibit this pathway during intestinal type 2 inflammatory disease, such as food allergy.
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