Antigen-specific regulatory T-cell responses against aeroantigens and their role in allergy

Abstract

The mucosal immune system of the respiratory tract is specialized to continuously monitor the external environment and to protect against invading pathogens, while maintaining tolerance to innocuous inhaled particles. Allergies result from a loss of tolerance against harmless antigens characterized by formation of allergen-specific Th2 cells and IgE. Tolerance is often described as a balance between harmful Th2 cells and various types of protective "regulatory" T cells. However, the identity of the protective T cells in healthy vs. allergic individuals or following successful allergen-specific therapy is controversially discussed. Recent technological progress enabling the identification of antigen-specific effector and regulatory T cells has significantly contributed to our understanding of tolerance. Here we discuss the experimental evidence for the various tolerance mechanisms described. We try to integrate the partially contradictory data into a new model proposing different mechanism of tolerance depending on the quality and quantity of the antigens as well as the way of antigen exposure. Understanding the basis of tolerance is essential for the rational design of novel and more efficient immunotherapies.

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

“…Detection of antigen-specific T cells in human samples is challenging because of their low frequency and difficulty to label T cells based on specificity (reviewed by Bacher and Scheffold 4,5 ). The frequently used in vitro pre-expansion of antigen-reactive T cells is highly error prone because of the unpredictable influence of the long-term culture (reviewed by Bacher and Scheffold 6 ).…”

“…On natural exposure, such as through breathing air, antigen intake is minimal. Calculations for inhaled A fumigatus, house dust mite, or plant pollen-derived proteins range from 5 to 50 ng/d, 1,6,115 and the uptake of individual allergens, such as Bet v 1, the major birch pollen allergen, was estimated to be less than 1 mg/y. 116 Such low doses of soluble proteins are generally likely to be ignored by the immune system because the critical threshold for T-cell activation might not be reached when taken up by antigen-presenting cells (APCs).…”

“…4,5 Contrary to T H 2 cells, which are readily detectable in allergic subjects, allergen-specific T cells are extremely rare in healthy subjects. Various technical approaches to overcome this problem, either through pre-expansion or (magnetic) pre-enrichment, have been used but resulted in different and partially contradictory results (reviewed by Bacher and Scheffold 6 ).…”

Functionally specialized human CD4+ T-cell subsets express physicochemically distinct TCRs

“…For example, individuals with Th1 deficiency are predisposed to recurrent bacterial and mycobacterial infections, and individuals with Th17 deficiency are predisposed to chronic mucocandidiasis [4][5][6] . In contrast, systemic autoimmunity is more common in individuals with Th17 overactivity and/or regulatory T cell (Treg) deficiency [7][8][9][10] , and allergy is more common in individuals with a similar imbalance between Th2 cells and Tregs [11][12][13] .…”

Nucleic Acid-Based Approaches for Tumor Therapy

“…Under homeostatic conditions Treg ensure tolerance towards self-antigens to prohibit autoimmunity [ 216 ], and against harmless antigens to prevent allergies [ 217 ]. Besides, as a negative feedback mechanism Treg are expanded and are also induced de novo in the course of immune reactions in order to limit immune responses and thereby to minimize tissue damages.…”