T Helper Cell Cytokines Modulate Intestinal Stem Cell Renewal and Differentiation
Name
nihms-1508993.pdf
Description
Accepted version
Size
4.26 MB
Format
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Checksum (MD5)
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Author(s)
Biton, Moshe
Haber, Adam L.
Rogel, Noga
Burgin, Grace
Beyaz, Semir
Schnell, Alexandra
Ashenberg, Orr
Su, Chien-Wen
Smillie, Christopher
Shekhar, Karthik
Date Issued
November 15, 2018
Journal
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
Abstract
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
MIT Department
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 MIT
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.cell.2018.10.008
