A 2025 preprint from the Belkaid laboratory proposed that constitutive expression of endogenous retroelements (EREs) by gut epithelial cells, and the reverse transcription of these elements into cDNA, is innately sensed by the cGAS/STING pathway and provides a tonic type I interferon signal required for tolerogenic dendritic cell function, food-specific regulatory T cell induction, and oral tolerance to dietary antigens. The work leaves open three linked questions: (i) whether a dominant tolerogenic role of ERE–cGAS/STING signaling is conserved across epithelial cell types and tissues, including those less exposed to external stimuli; (ii) whether constitutive or aberrant ERE expression contributes to the breakdown or diversion of oral tolerance during infection- or inflammation-driven responses; and (iii) whether pharmacological inhibition of retroelement reverse transcription — as occurs with pre-exposure prophylaxis (PrEP) regimens based on reverse transcriptase inhibitors — or altered innate sensing of EREs changes the etiology of allergic responses to food, particularly in individuals with celiac disease predisposition or at risk of T helper 2 (Th2)-skewed allergy. No resolution to any of these threads is known in the literature as of August 2026.

Background

Endogenous retroelements (EREs) are remnants of ancient retroviral infections and other transposable genetic elements that constitute a large fraction of mammalian genomes. Although long viewed as genomic parasites, many EREs are transcribed in a cell-type- and tissue-specific manner, and their nucleic-acid products can be detected by innate immune sensors. cGAS (cyclic GMP–AMP synthase) is a cytosolic enzyme that binds double-stranded DNA, including ERE-derived reverse-transcribed cDNA, and produces the second messenger cGAMP, which activates the adaptor protein STING (stimulator of interferon genes) on the endoplasmic reticulum and induces type I interferon (IFN-I) and other inflammatory programs. Oral tolerance is the active suppression of harmful immune responses to dietary antigens, acquired when antigen is first encountered through the gut; it depends on tolerogenic intestinal dendritic cells (antigen-presenting cells that promote non-responsiveness rather than effector immunity) and on the induction and tissue adaptation of antigen-specific regulatory T (Treg) cells, a suppressive T cell lineage marked by the transcription factor Foxp3. Its breakdown underlies food allergy and contributes to celiac-spectrum pathology, and viral infection is one documented trigger of tolerance loss (Bouziat et al., Science 2017). Prior work established that tonic innate and IFN-I signaling supports mucosal tolerance through microbiota- and metabolite-dependent routes: commensal bacteria sustain basal IFN-I signaling that preserves systemic tolerance (Vasquez Ayala et al., J Exp Med 2024), and the cyclic dinucleotide cGAMP together with IL-18 programs intestinal tolerance (Mertens et al., Immunity 2024). Separately, Lima-Junior et al. (Cell 2021) showed in the skin that cGAS/STING sensing of endogenous retrovirus-derived cDNA in keratinocytes orchestrates homeostatic and inflammatory responses to the microbiota. Against this backdrop, Rivera et al. (bioRxiv 2025, DOI 10.1101/2025.09.09.675192) reported that in the gut: basal ERE expression is epithelial-compartment-specific (highest in small intestine), independent of diet, microbial ligands, and microbiota; pharmacological inhibition of reverse transcription (tenofovir/emtricitabine), STING inhibition, blockade of the type I interferon receptor (IFNAR), or temporally restricted deletion of Sting in intestinal epithelial cells each abolished the induction of oral tolerance to a model dietary antigen in mice; and the effect was associated with impaired food-specific Treg differentiation and altered dendritic cell tolerogenic function. The authors conclude that ERE–cGAS/STING–IFN-I signaling in gut epithelial cells acts as a host-genome-intrinsic tonic signal licensing oral tolerance. Their discussion explicitly frames the unresolved issues examined here: conservation of this axis across epithelial cell types, its role in pathological tolerance breakdown, and the predicted — but untested — consequence of reverse transcriptase inhibitor exposure (for example, antiretroviral PrEP regimens) for food allergy and celiac-like disease in humans.

Problem Statement

Determine how general and how disease-relevant epithelial-intrinsic ERE–cGAS/STING innate sensing is in the control of immune tolerance to dietary antigens, as left open by Rivera et al. (bioRxiv 2025, DOI 10.1101/2025.09.09.675192). Three jointly contributing questions define the objective: (i) Conservation across epithelia — is the dominant tolerogenic role of ERE–cGAS/STING–IFN-I signaling demonstrated for gut epithelial cells — that signaling's capacity to provide a tonic tolerogenic cue, rather than the gut-restricted control of oral tolerance to dietary antigens — conserved across epithelial cell types and tissue compartments, including epithelia less exposed to external stimuli, or is it a specialization of highly stimulated barrier sites? (ii) Role in tolerance breakdown — does constitutive, and in some settings aberrant, ERE expression contribute to the diverse outcomes observed when infection or inflammation breaks or diverts oral tolerance, for example the loss of food-specific Treg induction seen during viral infection? (iii) Consequences of blocking the axis in humans — does pharmacological inhibition of retroelement reverse transcription, as occurs in antiretroviral pre-exposure prophylaxis (PrEP) regimens such as tenofovir/emtricitabine, or genetically or pharmacologically altered innate sensing of EREs, change the etiology or incidence of allergic responses to food, particularly in individuals with celiac disease predisposition or at elevated risk of T helper 2 (Th2)-skewed allergic responses? All three threads are mandatory: a complete resolution must address each of them, and resolving any single thread, or any subset of them, leaves the objective only partially answered. Each thread is settled by determining its stated question: thread (i) by determining whether that tolerogenic signaling role is conserved across epithelial cell types and tissue compartments or is restricted to highly stimulated barrier sites (the named epithelia illustrate the question rather than exhaust its domain); thread (ii) by determining whether constitutive or aberrant ERE expression contributes to the breakdown or diversion of oral tolerance under infection or inflammation; and thread (iii) by determining whether blocking retroelement reverse transcription or altering ERE sensing changes the etiology or incidence of food-allergic or celiac-spectrum outcomes in humans.

References

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