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Passing the baton in food tolerance: lymph-node priming and epithelial induction of Tr1 cells

Duan Ni , Ralph Nanan , Di Yu

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Vita > Cutting Edge > DOI: 10.15302/vita.2026.09.0076
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Passing the baton in food tolerance: lymph-node priming and epithelial induction of Tr1 cells

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T cells are central to food tolerance, particularly conventional CD4+FOXP3+ regulatory T cells (Tregs), whereas the physiological role of CD4+FOXP3–IL10+ type 1 regulatory (Tr1) cells remains less defined. Zhou et al. now show that intestinal epithelial cells selectively present food-derived, high-affinity MHCII-binding peptides to induce food antigen-specific Tr1 cells, revealing a complementary arm to Treg-mediated food tolerance.

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The intestinal immune system faces a continual balancing act: mounting protective responses against pathogens while remaining tolerant to the vast array of harmless dietary antigens. When this tolerance fails, intestinal homeostasis is disrupted and inflammatory disorders, most notably food allergies, can emerge1.
Multiple CD4+ T helper (Th) cell programmes contribute to food tolerance. CD4+FOXP3+ regulatory T cells (Tregs) are pivotal, restraining food allergic responses through mechanisms involving IL-10 and TGFβ2. Some Tregs arise from food antigen-primed, non-canonical hyporesponsive Th lineage-negative (Thlin–) cells3, while others can lose FOXP3 and convert to FOXP3–CD8αα+CD4+ intraepithelial lymphocytes (CD4IEL), another dietary antigen-responsive population that supports food tolerance4. Alongside these populations, CD4+FOXP3-IL10+ type 1 regulatory (Tr1) cells have emerged as a distinct tolerogenic subset responsive to dietary cues5. Yet their developmental origin, antigen specificity and division of labor with Tregs have remained unresolved.
The study by Zhou et al. now places Tr1 cells within a coherent cellular circuit for food tolerance6. Building on their prior findings that MHC class II (MHCII) expression by intestinal epithelial cells (IECs) protects against food allergy7, the authors show that IECs directly present food-derived antigen peptides to Tr1 cells. This interaction is unusually dynamic: isolated Tr1 cells rapidly lose IL-10, whereas cognate antigen presentation by IECs sustains it. The pathway unfolds in two anatomical steps. Food-specific naïve T cells are first primed by CD11c+ dendritic cells in mesenteric lymph nodes, then migrate to the small intestinal lamina propria, where re-encounter with cognate antigen on IECs drives the Tr1 programme (Fig. 1). FTY720 blockade of lymph-node egress reduces newly generated intestinal Tr1 cells, supporting this relay. Tr1 cells then appear to shuttle between lamina propria and epithelium with opposing circadian rhythms, creating a spatial link between feeding, epithelial antigen presentation and local IL-10 production.
Mechanistically, IECs do not process intact dietary proteins; rather, they display peptides generated during luminal digestion. In mice carrying the H2b MHC haplotype (I-Ab), mass spectrometry detects IEC-bound peptides from casein and whey, whose digested peptides show higher predicted MHCII affinity than those from gliadin, ovalbumin or peanut. Tr1 cells respond selectively to IEC-presented epitopes, and complementary loss-of-function experiments reveal a striking division of labor: IEC-MHCII-dependent Tr1 cells are required for tolerance to strong Tr1 inducers such as casein, whereas Tregs are more important for tolerance to weak Tr1 inducers like peanut. The authors then bypass this natural selectivity by packaging synthetic peanut allergen epitopes in positively glucosylated nanoparticles that target IECs. This enforced epithelial antigen presentation generates peanut-specific Tr1 cells and, in sensitized mice, reduces challenge-induced hypothermia, peanut-specific IgE/IgG1 and alleviates anaphylaxis.
These findings position Tr1 cells as a responsive, antigen-contingent layer of mucosal tolerance, tuned to the rhythm of food exposure rather than maintained as a fixed regulatory state. This distinction is important for food allergy. Tr1 cells are unlikely to act as an immediate brake on an acute IgE-mediated type I allergy involving mast cell degranulation and anaphylaxis, which usually happens within minutes to an hour after food allergen exposure; instead, their values may lie upstream, in conditioning the antigen-specific immune environment before re-exposure. Consistent with this interpretation, experimentally enforcing the IEC–Tr1 pathway did not simply neutralize an acute reaction, but reduced several features of subsequent peanut challenge.
The apparent division of labor between Treg and Tr1 cells also suggests a therapeutic opportunity: conventional oral immunotherapy (OIT) may engage tolerance to intact allergen through established regulatory pathways, while IEC-targeted peptide delivery could deliberately recruit the Tr1 arm. In support of clinical relevance, we recently found that peanut-allergic patients who achieved sustained tolerance after stopping OIT had increased circulating peanut-specific Tr1 cells8. Whether these blood populations mirror, derive from, or predict the intestinal Tr1 compartment remains an important question.
Tr1 cells may be particularly relevant to non-IgE-mediated, antigen-specific T-cell-driven type IV allergies. Type IV allergies include coeliac disease and food protein-induced enterocolitis, characterized by gastrointestinal mucosal inflammation developing slowly, usually over 48 h, after allergen exposure. In principle, repeated IEC presentation of dietary epitopes could divert potentially pathogenic antigen-specific CD4+ T cells towards an IL-10-producing Tr1 state and thereby restrain mucosal inflammation. Zhou et al. found gliadin to be a weak Tr1 inducer in their mouse system, but this may reflect the peptide-binding preferences of I-Ab rather than an intrinsic property of gliadin. Because HLA class II alleles are major determinants of coeliac-disease susceptibility, testing whether disease-associated human HLA molecules favor or resist IEC-driven Tr1 induction could be especially informative, both mechanistically and therapeutically.
The study also sharpens a longstanding question: what, precisely, defines an intestinal Tr1 cell? Their rapid gain and loss of IL-10 underscore a state that is functional and plastic rather than fixed by a single lineage marker. No defining transcription factor has yet been established. T-bet is expressed in intestinal Tr1 cells but is too broadly shared across CD4+ T cell states to serve as a specific marker5. c-Maf and aryl hydrocarbon receptor (AhR) contribute to IL-10 expression9,10, while eomesodermin (EOMES) and early growth response protein 2 (EGR2)11 mark many, but not all, Tr1 cells. The transcriptional heterogeneity observed by Zhou et al. is therefore likely to be biologically meaningful rather than merely technical variation. Their fate is equally unresolved. Th1 and Th17 cells can transdifferentiate into Tr1 cells12, but the reverse trajectory is less clear. When cognate IEC-MHCII stimulation is withdrawn and IL-10 falls, do Tr1 cells persist as quiescent antigen-experienced cells, revert towards their precursor state, or acquire alternative helper programmes? Temporal fate mapping will be needed to distinguish these possibilities.
Overall, Zhou et al. define an IEC–Tr1 axis that complements conventional Treg-mediated food tolerance and gives the title metaphor real mechanistic substance: lymph node antigen presenting cells prime the response, then pass the baton to the intestinal epithelium, where antigen re-encounter induces and sustains Tr1 cells (Fig. 1). This division of labor expands the framework of oral tolerance and opens a route to antigen-specific intervention in food allergy.

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The Author(s) 2026. Published by Higher Education Press. This is an Open Access article distributed under the terms of the CC BY license (https://creativecommons.org/licenses/by/4.0/).

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Ni, D., Nanan, R., Yu, D.  Passing the baton in food tolerance: lymph-node priming and epithelial induction of Tr1 cells  Vita https://doi.org/10.15302/vita.2026.09.0076 ()
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