Natural microbial exposure imposes layered constraints on epithelial and type 2 immunity

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Abstract
The tuft cell-ILC2 amplification circuit has emerged as a central paradigm of anti-helminth immunity in laboratory animals, driving the so-called weep and sweep response, required for parasite expulsion. Yet soil-transmitted helminths (STHs) commonly establish chronic infections in humans. Whether tuft cell expansion is required for parasite clearance under naturalistic conditions remains unknown. Here, using wildlings, a naturalized mouse model exposed from birth to complex microbial communities and pathogens, we re-investigated anti-STH immunity in the context of ecological realism. Following infection with Nippostrongylus brasiliensis , specific pathogen-free (SPF) mice mounted markedly amplified type 2 responses in both lung and intestine compared to wildlings. In the intestine, SPF mice mounted robust tuft cell expansion, IL-25 production, ILC2 accumulation, and goblet cell hyperplasia. In contrast, infected wildlings exhibited delayed parasite expulsion, limited tuft cell expansion, reduced IL-25 and ILC2 responses, and attenuated goblet cell expansion. Wildling tuft cells, but not goblet cells, displayed markedly reduced expansion in response to succinate or exogenous IL-13, indicating selective hypo-responsiveness of the epithelial sensory compartment. Microbial transfer into adult SPF mice selectively conferred tuft cell hypo-responsiveness without impairing ILC2 accumulation or goblet cell expansion. Tuft cell hypo-responsiveness in wildlings and FMT recipients was associated with enrichment of fermentative bacteria and increased levels of the short chain fatty acids acetate and propionate. Together, these findings indicate that ecological microbial exposure imprints systemic type 2 immunity during early-life, whereas epithelial responsiveness remains plastic and microbiome-dependent, thereby revealing regulatory constraints not evident under SPF conditions. One Sentence Summary: Our findings reveal that in a naturalized immune-microbiome context, intestinal tuft cells are surprisingly hypo-responsive, highlighting how environmental microbial exposure can calibrate type 2 immunity and helminth resistance.

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