Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.
Zuckerman Mind Brain Behavior Institute, Columbia University, NY, USA.
Sci Immunol. 2023 May 12;8(83):eade5019. doi: 10.1126/sciimmunol.ade5019.
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 , which encodes the protein OCA-T1, a transcriptional cofactor essential for tuft cell development. Epithelial crypts expressed a previously unannotated short isoform of 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 . Physiologically, isoform usage tuned innate type 2 immunity in the small intestine. Balb mice maintained responsiveness to helminth pathogens while ignoring commensal protists and reducing norovirus burdens.
化学感觉上皮簇细胞有助于屏障表面的固有免疫，但它们从上皮祖细胞分化的机制尚不清楚。在这里，我们利用近交系小鼠品系之间的差异来鉴定一种内在的上皮机制，该机制调节簇细胞分化，并调节小肠中的固有 2 型免疫。Balb/cJ（Balb）小鼠的肠道簇细胞比 C57BL/6J（B6）小鼠少，并且对簇细胞配体琥珀酸没有反应。这种差异的琥珀酸反应主要取决于 9 号染色体（Chr9）的 50-67Mb 区间，使得携带 B6 Chr9 区间的同基因 Balb 小鼠具有更高的簇细胞基线数量，并对琥珀酸有反应。Chr9 基因座包括 ，编码蛋白 OCA-T1，它是簇细胞发育所必需的转录共因子。上皮隐窝表达了以前未注释的短亚型的 ，预计使用不同的转录起始位点，并编码无功能的蛋白质。Balb 小鼠簇细胞数量少，导致琥珀酸反应缺失，这可以用短亚型的优先表达来解释，并且可以通过全长 的表达来挽救。在生理上， 亚型的使用调节了小肠中的固有 2 型免疫。Balb 小鼠保持对寄生虫病原体的反应能力，同时忽略共生原生动物，并减少诺如病毒的负担。
