Interactions between the Environment and Genetics determines immune variation in rewilded mice

Abstract

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.

Social association predicts immunological similarity in rewilded mice

“…The fact that social association predicts adaptive immune similarity in the MLNs but not the blood may reflect the role of the lymph nodes as sites of that antigen recognition. In our analysis of GxE effects on immune phenotype (25) we found that environment had more effect on immune cell composition in the blood than in the MLNs. However, here we are investigating within-strain heterogeneity in a single shared environment, so we may have a different predictor for something that would have been noise…”

“…We collected blood samples for Complete Blood Count (CBC) analysis prior to release and two weeks post-release, when we challenged a subset of mice with Trichuris muris, an intestinal nematode parasite. At five weeks post-release, prior to any shedding of T. muris eggs, we trapped out the mice for extensive immune phenotyping (25) and collected fecal samples for 16S microbiome analysis. We analyzed our data using Bayesian linear regression models with appropriate response variable distributions and priors to generate posterior probability distributions for the associations between predictors and response variables (see Methods).…”

“…cell profiles drawn from CBC measurements, CD4, CD8, and combined CD4 and CD8 T cell memory phenotypes (determined from cell surface expression of CD44 and CD62L as measured by flow cytometry) in blood and mesenteric lymph nodes (MLNs), B cell phenotypes in the B)A)MLNs drawn from flow cytometry, plasma cytokine concentrations, and MLN cytokine production from antigenic stimulation(25). To quantify similarity, we used Jaccard index for cell type distributions and Manhattan distance for cytokine measures.…”