Disruption of Oral Immune Tolerance by Respiratory Infections: Mechanisms of LungGut Immune Crosstalk

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

Food allergies are a growing public health concern, associated with significant morbidity, dietary restrictions, and rising healthcare costs. These disorders arise when the immune system mounts an inappropriate response to otherwise harmless dietary proteins, typically characterized by the production of allergen-specific IgE and the activation of mast cells and basophils upon re-exposure. Food allergy is initiated by a failure to establish or maintain oral tolerance—the physiological process by which the immune system learns to ignore food-derived antigens and remains unresponsive to ingested proteins. Loss of toral tolerance leads to the differentiation of CD4⁺ T cells into Th2 effector cells, which play a central role in allergic inflammation by producing IL-4, IL-5, and IL-13. These cytokines drive IgE class switching in B cells, recruit eosinophils, and alter epithelial barrier function, establishing a feed-forward loop that amplifies allergic sensitization and reactivity. Under homeostatic conditions, oral tolerance is induced in the gut-draining mesenteric lymph nodes (mesLN), where antigen-presenting cells (APCs) capture dietary antigens and present them to naïve CD4⁺ T cells. These T cells typically differentiate into peripheral regulatory T cells (pTregs), become anergic, or undergo apoptosis—mechanisms that collectively maintain immune hyporesponsiveness to food antigens. A critical unresolved question in the field is why some individuals fail to establish oral tolerance and instead develop food allergies. While genetic susceptibility contributes in a subset of patients, early-life environmental factors may also play a decisive role. However, the specific triggers and mechanisms that precipitate the breakdown of tolerance remain poorly defined. Food allergy most commonly begins in infancy and early childhood—a developmental window during which respiratory infections are also highly prevalent. Notably, viral respiratory infections such as influenza have been shown to disrupt gut epithelial integrity and alter the microbiota, suggesting that pulmonary inflammation may influence immune regulation in the gut. As part of our FY2025 efforts, this project investigates how respiratory infections affect the establishment of oral tolerance to food antigens. In agreement with previous studies, our FY2025 findings show that food-derived antigens can rapidly enter the bloodstream via the portal circulation. Specifically, oral administration of ovalbumin (OVA) results in detectable levels of OVA in the blood within 10 minutes, indicating swift systemic dissemination of dietary proteins. Although the mesLN are traditionally considered the primary site for oral tolerance induction, we found that circulating food antigens are also captured by dendritic cells in the lung-draining mediastinal lymph nodes (medLN), leading to the priming of food-specific CD4⁺ T cells in this gut-distal location. Under steady-state conditions, CD4⁺ T cells primed in both the mesLN and medLN exhibit a tolerized phenotype and fail to differentiate into effector cells. However, when oral proteins are administered following influenza virus infection, we observed a marked expansion of food antigen–specific CD4⁺ T cells in the medLN. These T cells acquired a T follicular helper (Tfh)-like phenotype, characterized by expression of PD-1, CXCR5, and Bcl-6. This shift was accompanied by the emergence of OVA-specific germinal center B cells and IgE⁺ plasma cells—indicative of tolerance breakdown and the initiation of allergic sensitization. These findings suggest that during respiratory inflammation, the medLN can become an aberrant site for the priming of food-specific immune responses, promoting pathogenic Tfh cell differentiation and IgE class switching. We are currently investigating the cellular and molecular mechanisms by which respiratory infections override the tolerogenic programming and redirect food-specific CD4⁺ T cells toward a pro-allergic fate. In parallel, we are assessing the relative contribution of these gut-distal responses to systemic food allergy development. This work has significant implications, as it identifies a novel mechanism by which lung inflammation can break oral tolerance and initiate food allergy. Understanding how respiratory infections reshape both the spatial dynamics and functional programming of food antigen responses will be essential for developing targeted strategies to prevent and treat food allergies—particularly during early childhood, a critical window for immune education and tolerance establishment.