The effect of regulatory T cells on tolerance to airborne allergens and allergen immunotherapy.

Forkhead box P3-positive regulatory T (Treg) cells are essential mediators of tolerance against self-antigens and harmless exogenous antigens. Treg cell deficiencies result in multiple autoimmune and allergic syndromes in neonates. How Treg cells affect conventional allergies against aeroantigens, which are restricted to a few specific proteins released from inhaled particles, remains controversial. The hallmarks of antigen-specific loss of tolerance are allergen-specific TH2 cells and IgE. However, difficulties in identifying the rare allergen-specific Treg cells have obscured the cellular basis of tolerance to aeroallergens, which is also a major obstacle for the rational design of novel and more efficient allergen-specific immunotherapies. Recent technological progress allowing characterization of allergen-specific effectors and Treg cells with minimal in vitro manipulation revealed their detailed contribution to tolerance. The data identified inhaled particles as immunodominant Treg cell targets in healthy and allergic subjects. Conversely, the supposed immunodominant major allergens being rapidly released from inhaled particles apparently do not actively induce tolerance but are ignored by the immune system. Here, the partially contradictory data on various allergen-specific T-cell types in healthy subjects, allergic patients, and patients undergoing allergen-specific immunotherapy are discussed and integrated into one model, postulating Treg cell-dependent and Treg cell-independent checkpoints of tolerance and allergy development.