Abstract
Oral tolerance is the process by which feeding of soluble proteins induces antigen-specific systemic immune unresponsiveness. Oral tolerance is thought to have a central role in suppressing immune responses to ‘harmless’ food antigens, and its failure can lead to development of pathologies such as food allergies or coeliac disease. However, on the basis of long-standing experimental observations, the relevance of oral tolerance in human health has achieved new prominence recently following the discovery that oral administration of peanut proteins prevents the development of peanut allergy in at-risk human infants. In this Review, we summarize the new mechanistic insights into three key processes necessary for the induction of tolerance to oral antigens: antigen uptake and transport across the small intestinal epithelial barrier to the underlying immune cells; the processing, transport and presentation of fed antigen by different populations of antigen-presenting cells; and the development of immunosuppressive T cell populations that mediate antigen-specific tolerance. In addition, we consider how related but distinct processes maintain tolerance to bacterial antigens in the large intestine. Finally, we outline the molecular mechanisms and functional consequences of failure of oral tolerance and how these may be modulated to enhance clinical outcomes and prevent disease.
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The work was supported by the German research foundation (DFG) Project-ID 403224013 – SFB 1382 (B06 to O.P).
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Glossary
- Anergy
-
When T cells encounter their cognate antigen in the absence of costimulation, they can become anergic. In this state, there is some evidence of activation, but there are no effector functions and the cell cannot proliferate or show other functions when restimulated with antigen. Anergic T cells also do not show active regulatory activity.
- Antigen-free diet
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A diet which lacks proteins or immunogenic peptides, with amino acids usually being the only source of nitrogen.
- Delayed-type hypersensitivity
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(DTH). Also known as type IV hypersensitivity, DTH is a form of immune reaction driven classically by CD4+ TH1 cells producing IFNγ, leading to activation of macrophages. The resulting production of nonspecific mediators such as TNF, IL-6, IL-1 and reactive oxygen intermediates is aimed at clearing pathogens, but it can also be an important cause of tissue damage.
- Exosomes
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Small vesicles with bilipid membranes derived from the cell surface or intracellular organelles such as endosomes, lysosomes or endoplasmic reticulum that are released into the surrounding environment. As well as membrane-bound molecules, they can contain other cellular material such as RNA, DNA and proteins which can transmit information to neighbouring cells.
- Gasdermin D
-
First described as the effector molecule released when a cell undergoes the inflammatory programmed cell death process of pyroptosis. In this situation, caspases activated downstream of the inflammasome result in cleavage of full-length gasdermin D, releasing an N-terminal form that forms pores in the cell membrane. The cell then dies owing to membrane leakage and pro-inflammatory mediators such as IL-1β are released through the pores. More recently, non-pore-forming roles of gasdermin D have been described and these include the caspase-dependent generation of a smaller fragment that can translocate to the nucleus and modify gene transcription.
- Oral tolerance
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Antigen-specific immunological hypo-responsiveness induced by feeding an antigen. It can affect both local immune function in the intestine and throughout the rest of the body.
- Peripherally induced Treg (pTreg) cells
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Similarly to thymic regulatory T cells (tTreg cells, also referred to as natural Treg cells), pTreg cells express FOXP3 and depend on this transcription factor for their development and functions. However, in contrast to tTreg cells, pTreg cells differentiate from conventional naive CD4+ T cells in secondary lymphoid organs under the influence of TGFβ and retinoic acid or when antigen is presented under conditions of metabolic stress. pTreg cells can express RORγt, but not Helios, and are usually specific for non-self-antigens. They are important in tolerance to foods, the microbiota and the fetus. By contrast, thymic Treg cells arise in the thymus, are self-reactive and express the Helios transcription factor. Both types of Treg cell control inflammatory effector immune responses in a number of ways, including through the production of inhibitory cytokines and the CTLA4-mediated removal of costimulatory molecules from the surface of antigen-presenting cells.
- Type 1 Treg cells
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A population of CD4+ T cells with regulatory function that do not express FOXP3, and the development of which is dependent on IL-10. They act by producing IL-10 and can also express IFNγ.
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Cerovic, V., Pabst, O. & Mowat, A.M. The renaissance of oral tolerance: merging tradition and new insights. Nat Rev Immunol (2024). https://doi.org/10.1038/s41577-024-01077-7
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DOI: https://doi.org/10.1038/s41577-024-01077-7
