T Helper Cell Cytokines Modulate Intestinal Stem Cell Renewal and Differentiation
Author(s)
Biton, Moshe; Haber, Adam L.; Rogel, Noga; Burgin, Grace; Beyaz, Semir; Schnell, Alexandra; Ashenberg, Orr; Su, Chien-Wen; Smillie, Christopher; Shekhar, Karthik; Chen, Zuojia; Wu, Chuan; Ordovas-Montanes, Jose Manuel; Alvarez, David; Herbst, Rebecca H.; Zhang, Mei; Tirosh, Itay; Dionne, Danielle; Nguyen, Lan T.; Xifaras, Michael; Shalek, Alexander K; von Andrian, Ulrich H.; Graham, Daniel B.; Rozenblatt-Rosen, Orit; Shi, Hai Ning; Kuchroo, Vijay; Yilmaz, Omer; Regev, Aviv; Xavier, Ramnik Joseph; ... Show more Show less
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In the small intestine, a niche of accessory cell types supports the generation of mature epithelial cell types from intestinal stem cells (ISCs). It is unclear, however, if and how immune cells in the niche affect ISC fate or the balance between self-renewal and differentiation. Here, we use single-cell RNA sequencing (scRNA-seq) to identify MHC class II (MHCII) machinery enrichment in two subsets of Lgr5⁺ ISCs. We show that MHCII⁺ Lgr5⁺ ISCs are non-conventional antigen-presenting cells in co-cultures with CD4⁺ T helper (Th) cells. Stimulation of intestinal organoids with key Th cytokines affects Lgr5⁺ ISC renewal and differentiation in opposing ways: pro-inflammatory signals promote differentiation, while regulatory cells and cytokines reduce it. In vivo genetic perturbation of Th cells or MHCII expression on Lgr5⁺ ISCs impacts epithelial cell differentiation and IEC fate during infection. These interactions between Th cells and Lgr5⁺ ISCs, thus, orchestrate tissue-wide responses to external signals. Intestinal stem cells act as non-conventional antigen presenting cells, and these interactions with T helper cells modulate ISC renewal and differentiation to shape the intestine. Keywords: gut biology; intestinal stem cells; ISCs; T helper; Th; mucosal immunity; MHC class II; MHCII; tuft cells; T regulatory; Treg; single cell RNA-seq; scRNA-seq; epithelial differentiation; stem cell renewal
Date issued
2018-11-15Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science; Ragon Institute of MGH, MIT and Harvard; Massachusetts Institute of Technology. Center for Microbiome Informatics and Therapeutics; Koch Institute for Integrative Cancer Research at MITJournal
Cell
Publisher
Elsevier Science Ltd.
Citation
Biton, Moshe et al. "T Helper Cell Cytokines Modulate Intestinal Stem Cell Renewal and Differentiation." Cell, 175, 5 (November 2018): 1307-1320 © 2018 Elsevier Inc.
Version: Author's final manuscript
ISSN
0092-8674