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Retroelements orchestrate gut tolerance

Nature Reviews Immunology volume 25, page 867 (2025)Cite this article

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Oral tolerance is a fundamental process that prevents inflammatory responses to dietary antigens, and its breakdown underlies food allergies and other inflammatory diseases of the gut. Tolerogenic conventional dendritic cells (cDCs) and regulatory T (Treg) cells are key to maintaining this tolerance but the upstream mechanisms remain poorly understood.

A recent preprint (not peer reviewed) by Rivera et al. reveals an unexpected link between endogenous retroelements and oral tolerance. The authors report that retroelement-encoded reverse transcriptase (RT) activity sustains cGAS–STING and type I interferon (IFN-I) signalling in the gut, which are required for oral tolerance. The authors used well-established mouse models of oral tolerance, in which mice are first exposed orally to a model antigen during a tolerization phase before immunization and challenge with the antigen at peripheral sites. Non-tolerized mice mounted inflammatory responses characterized by swelling and immune cell infiltration at the challenge site, as did mice treated with RT inhibitors during the tolerization phase, which indicates that RT activity is required for the induction of oral tolerance.

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  1. Preprint Club, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Laura Rosenberg & Nicolas Vabret

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  1. Laura Rosenberg
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  2. Nicolas Vabret
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Correspondence to Laura Rosenberg.

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Rosenberg, L., Vabret, N. Retroelements orchestrate gut tolerance. Nat Rev Immunol 25, 867 (2025). https://doi.org/10.1038/s41577-025-01243-5

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  • DOI: https://doi.org/10.1038/s41577-025-01243-5

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