Housing laboratory mice in a natural environment uncovers genetic and environmental contributions to immune variation.

The relative contributions of genetic and environmental factors to variation in immune responses are still poorly understood. Here, we performed a deep phenotypic analysis of immunological parameters of laboratory mice released into an outdoor enclosure, carrying susceptibility genes (Nod2 and Atg16l1) implicated in the development of inflammatory bowel diseases. Variations of immune cell populations were largely driven by environment, whereas cytokine production showed a stronger genetic component, but this genetic effect was reduced after exposure to the wild environment. Multi-omic models identified transcriptional signatures associated with differences in T cell populations. Sub-networks associated with responses against Candida albicans and Bacteroides vulgatus are also coupled with rewilding. Hence, exposing laboratory mice of different genetic backgrounds to the outdoor environment can uncover important contributors to immune variation.