T helper cell cytokines modulate intestinal stem cell renewal and differentiation

Contributors: Moshe Biton*, Adam L. Haber*, Noga Rogel*, Grace Burgin, Semir Beyaz, Alexandra Schnell, Orr Ashenberg, Christopher Smillie, Karthik Shekhar, Zuojia Chen, Chuan Wu, Jose Ordovas-Montanes, David Alvarez, Rebecca H. Herbst, Chien wen Su, 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§ and Ramnik J. Xavier§

Contact: mbiton@broadinstitute.org

GEO: GSE106510

Summary:

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-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.