T Helper Cell Cytokines Modulate Intestinal Stem Cell Renewal and Differentiation

Moshe Biton; Adam L Haber; Noga Rogel; Grace Burgin; Semir Beyaz; Alexandra Schnell; Orr Ashenberg; Chien-Wen Su; Christopher Smillie; Karthik Shekhar; Zuojia Chen; Chuan Wu; Jose Ordovas-Montanes; David Alvarez; Rebecca H Herbst; Mei Zhang; Itay Tirosh; Danielle Dionne; Lan T Nguyen; Michael E Xifaras; Alex K Shalek; Ulrich H von Andrian; Daniel B Graham; Orit Rozenblatt-Rosen; Hai Ning Shi; Vijay Kuchroo; Omer H Yilmaz; Aviv Regev; Ramnik J Xavier

doi:10.1016/j.cell.2018.10.008

T Helper Cell Cytokines Modulate Intestinal Stem Cell Renewal and Differentiation

Cell. 2018 Nov 15;175(5):1307-1320.e22. doi: 10.1016/j.cell.2018.10.008. Epub 2018 Nov 1.

Authors

Moshe Biton¹, Adam L Haber², Noga Rogel², Grace Burgin², Semir Beyaz³, Alexandra Schnell⁴, Orr Ashenberg², Chien-Wen Su⁵, Christopher Smillie², Karthik Shekhar², Zuojia Chen⁴, Chuan Wu⁴, Jose Ordovas-Montanes⁶, David Alvarez⁷, Rebecca H Herbst⁸, Mei Zhang⁵, Itay Tirosh⁹, Danielle Dionne², Lan T Nguyen², Michael E Xifaras¹⁰, Alex K Shalek⁶, Ulrich H von Andrian⁷, Daniel B Graham¹¹, Orit Rozenblatt-Rosen², Hai Ning Shi⁵, Vijay Kuchroo¹², Omer H Yilmaz¹³, Aviv Regev¹⁴, Ramnik J Xavier¹⁵

Affiliations

¹ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
² Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³ The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
⁴ Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
⁶ Institute for Medical Engineering & Science (IMES) and Department of Chemistry, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA.
⁷ Department of Microbiology & Immunobiology and Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA.
⁸ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02114, USA.
⁹ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
¹⁰ The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA.
¹¹ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
¹² Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
¹³ The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁴ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02140, USA. Electronic address: aregev@broadinstitute.org.
¹⁵ Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Microbiome informatics and Therapeutics, MIT, Cambridge, MA 02139, USA. Electronic address: xavier@molbio.mgh.harvard.edu.

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.

Keywords: ISCs; MHC class II; MHCII; T helper; T regulatory; T(reg); Th; epithelial differentiation; gut biology; intestinal stem cells; mucosal immunity; scRNA-seq; single cell RNA-seq; stem cell renewal; tuft cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation* / drug effects
Cell Self Renewal* / drug effects
Cytokines / pharmacology
Epithelial Cells / cytology
Epithelial Cells / metabolism
Female
Histocompatibility Antigens Class II / metabolism
Immune System / metabolism
Interleukin-10 / metabolism*
Intestines / cytology
Intestines / microbiology
Male
Mice
Mice, Inbred C57BL
Organoids / cytology
Organoids / drug effects
Organoids / metabolism
Receptors, G-Protein-Coupled / metabolism
Salmonella enterica / pathogenicity
Stem Cells / cytology*
Stem Cells / metabolism
T-Lymphocytes, Helper-Inducer / cytology
T-Lymphocytes, Helper-Inducer / metabolism*

Substances

Cytokines
Histocompatibility Antigens Class II
Lgr5 protein, mouse
Receptors, G-Protein-Coupled
Interleukin-10

Abstract

Publication types

MeSH terms

Substances

Grants and funding