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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.