Highlights d IGF-1 and FGF-2 improve human intestinal organoid plating and genome editing efficiencies d Organoids maintain self-renewal and multi-differentiation capacity in refined condition d Refined condition enables long-term culture of healthy and diseased intestinal organoids d Human small intestinal crypts and organoids compared with droplet-based scRNA-seq
Summary
Innate lymphoid cells (ILCs) play key roles in host defense, barrier integrity, and homeostasis, and they mirror adaptive CD4+ T helper (Th) cell subtypes in both usages of effector molecules and transcription factors. To better understand the relationship between ILC subsets and their Th cells counterparts, we measured genome-wide chromatin accessibility. We find that chromatin in proximity to effector genes is selectively accessible in ILCs prior to high-level transcription upon activation. Accessibility of these regions is acquired in a stepwise manner during development and changes little after in vitro or in vivo activation. Conversely, dramatic chromatin remodeling occurs in naïve CD4+ T cells during Th cell differentiation using a type 2-infection model. This alteration results in a substantial convergence of Th2 cells toward ILC2 regulomes. Our data indicate extensive sharing of regulatory circuitry across the innate and adaptive compartments of the immune system, in spite of their divergent developing pathways.
Imbalance in gut bacterial composition provokes host proinflammatory responses causing diseases such as colitis. Colonization with a mixture of Clostridium species from clusters IV and XIVa was shown to suppress colitis through the induction of IL-10-producing regulatory T (Treg) cells. We demonstrate that a distinct Clostridium strain from cluster I, Clostridium butyricum (CB), prevents acute experimental colitis in mice through induction of IL-10, an anti-inflammatory cytokine. However, while CB treatment had no effect on IL-10 production by T cells, IL-10-producing F4/80(+)CD11b(+)CD11c(int) macrophages accumulated in the inflamed mucosa after CB treatment. CB directly triggered IL-10 production by intestinal macrophages in inflamed mucosa via the TLR2/MyD88 pathway. The colitis-preventing effect of CB was negated in macrophage-specific IL-10-deficient mice, suggesting that induction of IL-10 by intestinal macrophages is crucial for the probiotic action of CB. Collectively, CB promotes IL-10 production by intestinal macrophages in inflamed mucosa, thereby preventing experimental colitis in mice.
Highlights d Single-cell analysis reveals heterogeneity of ILC2 responses to N. brasiliensis d Il5 hi ILC2s express CGRP and its receptor following helminth infection d CGRP modulates type 2 cytokine production by ILC2s induced by alarmin and NMU d CGRP constrains the magnitude of innate type 2 responses following helminth infection
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