A history of microbial exposures has a temporally limited inhibitory effect on mouse lung ILC2 responses to a fungal allergen

Abstract

Abstract The ability of some microbes and their products to restrain the immune response to allergens has been extensively studied and is a key element of the hygiene hypothesis. However, it is unclear whether a modulated immune response relates to recent microbial exposure, or whether a diverse infectious history promotes sustained changes in reactivity to allergens. Thus, we explored how prior microbial experience in “dirty” mice affected innate immune responses to an airway fungal allergen. Dirty mice were generated by cohousing laboratory mice with pet store mice for at least 60 days to allow for physiological transmission of microbes. Despite changes induced in many immune cell populations, lung type 2 innate lymphoid cell (ILC2) numbers and phenotype were unaltered by cohousing. Short term (4.5 hour) production of the type 2 cytokines IL-5 and IL-13 in response to Alternaria alternata extract was consistently depressed in dirty mice relative to specific pathogen free (SPF) and germ-free animals. This correlated with diminished release of IL-33, an alarmin that activates ILC2, in dirty mice. Nevertheless, at a later timepoint (24 hours) or after repeated Alternaria exposure, the influx of eosinophils, neutrophils and T cells into the lungs was similar in dirty and SPF mice. Our data therefore indicate that a history of robust and diverse microbial exposure delays but ultimately does not restrain development of a type 2 response to airway allergens, in contrast to the established inhibitory effects of acute exposure to certain microbes and their products.