Antigen-specific Treg cells in immunological tolerance: implications for allergic diseases

Abstract

Allergic diseases are chronic inflammatory disorders in which there is failure to mount effective tolerogenic immune responses to inciting allergens. The alarming rise in the prevalence of allergic diseases in recent decades has spurred investigations to elucidate the mechanisms of breakdown in tolerance in these disorders and means of restoring it. Tolerance to allergens is critically dependent on the generation of allergen-specific regulatory T (Treg) cells, which mediate a state of sustained non-responsiveness to the offending allergen. In this review, we summarize recent advances in our understanding of mechanisms governing the generation and function of allergen-specific Treg cells and their subversion in allergic diseases. We will also outline approaches to harness allergen-specific Treg cell responses to restore tolerance in these disorders.

Keywords: Regulatory T Cells; allergy; antigen-specific.

Figure 1.. Generation of natural regulatory T (nTreg) and induced Treg (iTreg) cells.

Schematic representation of nTreg and iTreg cell developmental pathways. Naturally occurring Treg cells develop upon intermediate-avidity interaction between developing thymocytes and self-antigen-presenting medullary epithelial cells. High-level expression of Neuropilin (Nrp-1) and Helios is maintained on nTreg cells after their migration from the thymus. Naïve conventional T cells that have undergone positive and negative selection in the thymus and have low avidity for self-antigens may develop into iTreg cells upon encountering antigens presented by tolerance-inducing antigen-presenting cells in specialized niches in the periphery. These cells express low levels of Helios or Nrp-1. Both nTreg and peripheral Treg cells are able to suppress CD4 ⁺ effector helper T 2 (TH2) cell responses. High-avidity T-cell receptor interaction in the thymus results in cytolytic T cells (negative selection). DP, double positive; IRF4, interferon gamma regulatory factor 4.

Figure 2.. Mucosal tolerance in the gut and its breakdown in food allergy.

( Left) Under homeostatic conditions, CX3CR1 ⁺ macrophages sample components of the gut lumen and transfer luminal antigens to IRF8 ⁺CD103 ⁺ dendritic cells (DCs), which in turn promote the formation of antigen-specific induced regulatory T (iTreg) cells. iTreg cells expressing retinoid-related orphan receptor gamma t (RoR-γt) may regulate tolerance to dietary antigens by a range of mechanisms, including the suppression of mast cell activation. iTreg cells may also prevent the conversion of naïve CD4 ⁺ T cells to antigen-specific helper T 2 (TH2) cells. ( Right) Under food allergic conditions, CD11b ⁺CD103 ^– DCs encounter allergens that are made more accessible by a permeable epithelial barrier. Allergen-presenting DCs drive the differentiation of naïve T cells into allergen-specific TH2 cells expressing the interleukin-4 receptor (IL-4R). iTreg cells also acquire a TH2 cell-like phenotype characterized by increased GATA3 and IRF4 expression and the release of IL-4 and IL-13. These ‘pathogenic’ Treg cells are unable to suppress mast cell activation through engagement of the OX40-OX40 ligand pathway. Binding of IgE to the high-affinity receptor for IgE (FcεRI) leads to uninhibited mast cell degranulation and IL-4 production. IRF8, interferon gamma regulatory factor 8; SCFA, short-chain fatty acid; TGFβ, transforming growth factor beta.

Figure 3.. Induced regulatory T (iTreg) cell subversion by the asthma-promoting IL-4Rα-R576 variant.

Schematic representation of pathways mediating iTreg cell subversion by the asthma-promoting IL-4Rα-Q76R variant. The glutamine to arginine substitution at position 576 of IL-4Rα chain allows recruitment of the protein adaptor GRB2 upon receptor activation. GRB2 activates downstream MAP kinase cascades, including extracellular signal–regulated kinases, which drive IL-6 production by activating the transcription factors NF-κB and C/EBP-β, and p38 MAP kinase, which activates IL-13 production. Newly formed antigen-specific iTreg cells are subsequently destabilized, resulting in the generation of excessive TH2 and TH17 cell responses that promote severe airway hyper-responsiveness.