@article{12e43fe514ee43459ec5b9857658f3a5,
title = "Genetic mapping reveals Pou2af2/OCA-T1–dependent tuning of tuft cell differentiation and intestinal type 2 immunity",
abstract = "Chemosensory 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. Most of this differential succinate response was determined by the 50- to 67-Mb interval of chromosome 9 (Chr9), such that congenic Balb mice carrying the B6 Chr9 interval had elevated baseline numbers of tuft cells and responded to succinate. The Chr9 locus includes Pou2af2, which encodes the protein OCA-T1, a transcriptional cofactor essential for tuft cell development. Epithelial crypts expressed a previously unannotated short isoform of Pou2af2 predicted to use a distinct transcriptional start site and encode a nonfunctional protein. Low tuft cell numbers and the resulting lack of succinate response in Balb mice were explained by a preferential expression of the short isoform and could be rescued by expression of full-length Pou2af2. Physiologically, Pou2af2 isoform usage tuned innate type 2 immunity in the small intestine. Balb mice maintained responsiveness to helminth pathogens while ignoring commensal Tritrichomonas protists and reducing norovirus burdens.",
author = "Nadjsombati, {Marija S.} and Natalie Niepoth and Webeck, {Lily M.} and Kennedy, {Elizabeth A.} and Jones, {Danielle L.} and Billipp, {Tyler E.} and Baldridge, {Megan T.} and Andres Bendesky and {von Moltke}, Jakob",
note = "Funding Information: We thank all members of the von Moltke lab for helpful discussion and input on this manuscript. We thank D. Hailey and the Garvey Cell Imaging Lab in the Institute for Stem Cell and Regenerative Medicine for microscopy support; the mouse husbandry staff in the UW SLU vivarium; V. Gersuk, K. O{\textquoteright}Brien, and the Benaroya Research Institute Genomics Core for help with RNA sequencing; and M. F. Fontana for helpful comments on the manuscript. Flow cytometry data were acquired through the University of Washington, Cell Analysis Facility Shared Resource Lab, with NIH award 1S10OD024979-01A1 funding for the Symphony A3. M.S.N. was supported by a University of Washington Immunology Training Grant T32 AI106677 and by the UW Immunology Department Titus Fellowship. T.E.B. was supported by the UW Immunology Fellowship, and D.L.J. was a UW Mary Gates scholar. Work at Columbia University was supported by NIH R35GM143051, Sloan Foundation Fellowship, Klingenstein-Simons Fellowship (all to A.B.). A.B. and J.v.M. are Searle Scholars. J.v.M. is a Burroughs Wellcome Investigator in the Pathogenesis of Infectious Disease. Work at Washington University was supported by R01AI139314 (to M.T.B.) and F31AI167499 (to E.A.K.). Work at the University of Washington was supported by NIH DP2OD024087 and R01AI167923. Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved.",
year = "2023",
month = may,
doi = "10.1126/SCIIMMUNOL.ADE5019",
language = "English",
volume = "8",
journal = "Science immunology",
issn = "2470-9468",
number = "83",
}