Adaptive immunity shapes innate and epithelial cell landscapes by silencing tonic IFN-γ in innate lymphoid cells during homeostasis

During homeostasis, innate and epithelial cells undergo continuous maturation, shaped by microbial, molecular and cellular interactions. While these cells influence adaptive immunity during steady-state conditions, the reciprocal homeostatic role of adaptive immune cells in the maturation and function of innate and epithelial cells remains underexplored. Here, through computational approaches and murine models, we establish that adaptive immunity shapes innate immune and epithelial homeostatic landscapes. Mechanistically, adaptive immunity acts as a brake on type 1 polarization and diversification of innate lymphocytes (ILCs). Without adaptive immunity, the innate cellular interactions within the mesenteric lymph nodes are dominated by an interferon-gamma (IFNγ) signaling network. Moreover, the innate immune and epithelial cells follow distinct phenotypic and functional trajectories, including ILCs acquiring myeloid markers, monocytes adopting an inflammatory path, and colonic epithelial cells expressing altered antimicrobial peptides and losing Paneth-like features. Depleting ILCs, abolishing IFNγ signaling, or restoring adaptive immunity reduces these IFNγ-driven changes. Thus, our findings highlight a homeostatic function of adaptive immunity in modulating innate and epithelial cell communication, diversity, composition, function, and differentiation, notably by limiting ILC-derived IFNγ.