Mechanisms of immune tolerance relevant to food allergy

Abstract

The intestine has an unenviable task: to identify and respond to a constant barrage of environmental stimuli that can be both dangerous and beneficial. The proper execution of this task is central to the homeostasis of the host, and as a result, the gastrointestinal tract contains more lymphocytes than any other tissue compartment in the body, as well as unique antigen-presenting cells with specialized functions. When antigen is initially encountered through the gut, this system generates a robust T cell-mediated hyporesponsiveness called oral tolerance. Although seminal observations of oral tolerance were made a century ago, the relevant mechanisms are only beginning to be unraveled with the use of modern investigational techniques. Food allergy is among the clinical disorders that occur from a failure of this system, and therapies that seek to re-establish tolerance are currently under investigation.

Figure 1. Immunity, not tolerance, occurs after allergen exposure in early life

Neonatal mouse pups were exposed to ovalbumin (OVA) via intra-amniotic injection 24–36 hours prior to birth or fed OVA (1 mg/gram body weight) or saline at day 1, 3, 7, 14, or 42. When rechallenged, animals exposed to OVA prior to the seventh day of life did not develop tolerance but instead robust humoral and cell-mediated immune responses, which persisted up to 14 weeks. Although it had long been known that tolerance was the default response to oral antigen administration in adult mice, these experiments demonstrated that oral exposure in early life could result in active immunologic priming rather than suppression.

Figure 2. Microenvironmental signals initiate tolerogenic dendritic cell responses

Oral tolerance depends on CD103+ mucosal dendritic cells encountering luminal antigens and transporting them to the mesenteric lymph nodes. This process requires CCR7 and is positively influenced by local factors such as retinoic acid, TGF-β, and IDO. CD103+ dendritic cells conditioned by these stimuli then interact with cognate T cells to actively suppress immune reactivity.

Figure 3. T lymphocytes are the ultimate effectors of oral tolerance

Once antigens pass through the gut epithelium and are taken up, processed, and presented by antigen-presenting cells on MHC II, one of several fates is possible, depending on the conditions present: (a), An active immune response ensues when the T cell receives input from its co-stimulatory molecule CD28, which binds CD80/86 on the antigen-presenting cell; (b), Reactive clones are rendered anergic or deleted if the TCR-peptide-MHC interaction occurs without costimulation, or in the presence of FAS-FASL interaction, respectively; (c), Inducible or adaptive T regulatory cells, which express the gut-homing receptors CCR9 and α4β7, are generated in the mesenteric lymph node by interactions with tolerogenic dendritic cells. Tr1 cells are formed in the presence of the suppressive cytokine IL-10 and go on to themselves produce IL-10, whereas T_H3 cells produce TGF-β.