Granulocyte-macrophage colony-stimulating factor (GM-CSF) protects the intestinal mucosa during ulceration in Crohn's disease (CD), but the evidence for this protective role comes from larval zebrafish, which lack functional adaptive immunity. In CD, innate lymphoid cells (ILCs) and adaptive T helper (Th) cells can both produce GM-CSF, but on the receiving side Th cells respond to it directly whereas ILCs are modulated only indirectly; mouse studies attribute opposite, context-dependent roles to GM-CSF from each compartment. The open problem left by Morrison et al. (2026) is to dissect the relative contributions of innate versus adaptive lymphocytes to GM-CSF-mediated mucosal protection in models with a functional adaptive immune system, resolving which lymphocyte compartments supply the protective GM-CSF signal and which must receive it.

Background

Granulocyte-macrophage colony-stimulating factor (GM-CSF, gene CSF2) is a secreted cytokine that signals through a receptor whose beta subunit is encoded by CSF2RB, activating the transcription factor STAT5 (signal transducer and activator of transcription 5, measured as phosphorylated pSTAT5) in myeloid cells such as monocytes and macrophages. Innate lymphoid cells (ILCs) are tissue-resident, lymphocyte-lineage cells that lack antigen-specific T-cell receptors; in the intestine, ILC3s produce IL-22 (an epithelial-repair cytokine) and GM-CSF, while inflammatory ILC1s expand in inflamed Crohn's disease (CD) mucosa. T helper (Th) cells are the adaptive counterparts, including Th17 cells that also produce GM-CSF. The relevance of this axis to CD is supported by human genetics: a frameshift variant in CSF2RB is the second most prevalent CD-associated frameshift variant in the Ashkenazi Jewish population and reduces GM-CSF-induced monocyte signaling (Chuang et al. 2016), CSF2RB is strongly associated with CD in East Asian populations (Liu et al. 2023), and neutralizing anti-GM-CSF autoantibodies predict complicated CD years before diagnosis (Mortha et al. 2022). Recombinant human GM-CSF (sargramostim) showed signals of clinical benefit in a randomized trial in active CD (Korzenik et al. 2005), but the mechanism was never attributed to a lymphocyte compartment. Mechanistic work in mice has produced opposite, context-dependent conclusions: RORγt-positive ILCs are the primary intestinal GM-CSF source at homeostasis and support macrophage-ILC crosstalk (Mortha et al. 2014), ILC3-derived GM-CSF is pathogenic in innate-driven colitis by recruiting inflammatory monocytes (Pearson et al. 2016) yet protective in Clostridioides difficile infection by sustaining neutrophils (Fachi et al. 2024), and GM-CSF-producing Th17 cells are pathogenic in dextran sodium sulfate (DSS, a chemical epithelial-injury) colitis (Ariki et al. 2023). Morrison et al. (2026) combined Xenium in-situ spatial transcriptomics (a method that measures gene expression of single cells while preserving their locations in tissue) on inflamed versus uninvolved ileal CD tissue with a novel csf2rb-knockout larval zebrafish DSS injury model. They found GM-CSF transcripts enriched in ulcer granulation tissue, STAT5 phosphorylation in lymphocytes adjacent to macrophage aggregates, and a protective effect of recombinant human GM-CSF that restrains ILC1 expansion, maintains ILC3s and their IL-22 production, and depends on Csf2rb. Because larval zebrafish lack functional adaptive immunity, this dissection could only capture the innate (myeloid-ILC) side of the axis; ILCs themselves lack CSF2RA/B, so the ILC effects are inferred to be indirect, likely through monocytes via retinoic acid (a vitamin-A-derived metabolite that monocytes can supply to tune ILC3s). How the protective GM-CSF axis operates when adaptive Th cells — which both produce GM-CSF and depend on GM-CSF-producing innate circuits (Samarakoon et al. 2016) — are present, as in human CD, remains untested.

Problem Statement

In models of intestinal inflammation with a functional adaptive immune system (for example adaptive-competent mice or adult zebrafish, complemented by human intestinal tissue), dissect the relative contributions of innate lymphoid cells versus adaptive T helper lymphocytes to the protective effect of GM-CSF on the inflamed mucosa. Concretely, determine (i) on the source side, the relative contribution of each compartment — ILC3s versus GM-CSF-producing Th cells — to the protective GM-CSF signal when both are present, and (ii) on the responder side, which lymphoid and myeloid compartments must receive or be indirectly modulated by GM-CSF signaling (via CSF2RB/STAT5 in myeloid and T cells, and indirectly in ILCs through monocyte-derived mediators such as retinoic acid) for the protective outcome observed by Morrison et al. (2026): restrained ILC1 expansion, maintained ILC3s and IL-22 production, reduced epithelial injury, and blunted induction of pro-inflammatory cytokines (tnfa, il1b, osm, and ifng1-1 in the larval zebrafish model).

References

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