Genetic mapping revealsPou2af2-dependent tuning of tuft cell differentiation and intestinal type 2 immunity

Abstract

AbstractChemosensory epithelial tuft cells contribute to innate immunity at barrier surfaces, but their differentiation from epithelial progenitors is not well understood. Here we exploited differences between inbred mouse strains to identify an epithelium-intrinsic mechanism that regulates tuft cell differentiation and tunes innate type 2 immunity in the small intestine. Balb/cJ (Balb) mice had fewer intestinal tuft cells than C57BL/6J (B6) mice and failed to respond to the tuft cell ligand succinate. A majority of this differential succinate response was determined by a single genetic locus from 50-67Mb on chromosome 9 (Chr9). Congenic Balb mice carrying the B6 Chr9 locus had elevated baseline numbers of tuft cells and responded to succinate. The Chr9 locus includesPou2af2, a transcriptional cofactor essential for tuft cell development. Epithelial crypts expressed a previously unannotated short isoform ofPou2af2that uses a novel transcriptional start site and encodes a non-functional protein. Low tuft cell numbers and the resulting lack of succinate response in Balb mice was explained by a preferential expression of the short isoform. Physiologically, differentialPou2af2isoform usage tuned innate type 2 immunity in the small intestine. Balb mice maintained responsiveness to helminth pathogens while ignoring commensalTritrichomonasprotists and reducing norovirus burdens.One Sentence SummaryGenetic mapping identifiesPou2af2isoform usage as a novel regulator of tuft cell differentiation that tunes intestinal innate type 2 immunity.