Regulatory T cells in allergic diseases

Abstract

The pathogenesis of allergic diseases entails an ineffective tolerogenic immune response to allergens. Regulatory T (Treg) cells play a key role in sustaining immune tolerance to allergens, yet mechanisms by which Treg cells fail to maintain tolerance in patients with allergic diseases are not well understood. We review current concepts and established mechanisms regarding how Treg cells regulate different components of allergen-triggered immune responses to promote and maintain tolerance. We will also discuss more recent advances that emphasize the "dual" functionality of Treg cells in patients with allergic diseases: how Treg cells are essential in promoting tolerance to allergens but also how a proallergic inflammatory environment can skew Treg cells toward a pathogenic phenotype that aggravates and perpetuates disease. These advances highlight opportunities for novel therapeutic strategies that aim to re-establish tolerance in patients with chronic allergic diseases by promoting Treg cell stability and function.

Keywords: Asthma; IL-4; T(H)2 cells; food allergy; forkhead box P3; regulatory T cells.

Fig 1. Natural and inuced Foxp3⁺ T_Reg cells subsets

The T_Reg cell pool is composed by two different sub-populations, nT_Reg and iT_Reg cells, both expressing the transcription factor Foxp3 crucial for their development and regulatory functions. Foxp3⁺ Nrp-1^high Helios^high nT_Reg cells arise in the thymus and mediate tolerance to self- antigens. Foxp3⁺ Nrp-1^low Helios^low iT_Reg cells, which mediate tolerance to foreign antigens, are induced extra-thymically from naïve CD4⁺ Foxp3⁻ T_conv cells in the presence of TCR stimulation, TGF-β and RA by either CD103⁺ DCs at the intestinal mucosa or F4/80⁺ CD11c⁺ macrophages at the airways epithelial surfaces.

Fig 2. Mechanisms of Foxp3⁺ T_Reg cell-mediated suppression

Foxp3⁺ T_Reg cells mediate tolerance to allergens by diverse suppressive mechanisms. These include T cell cytolysis by a granzyme dependent mechanism, IL-2 deprivation, production of inhibitory cytokines including IL-10, IL-35 and TGF-β capable of blocking the proliferation of T_eff cells and down-modulation of antigen presenting cells (APCs) via LAG-3-MHC II and CTLA-4-CD80/CD86 interactions.

Fig 3. Regulation and suppression of allergic innate immune responses by T_Reg cells

T_Reg cells control innate immune cell subsets involved in promoting allergy. T_Reg cells block mast cell activation and the release of pre-formed anaphylactic mediators through OX40-OX40L mediated interactions. T_Reg cells also impede the IL-33-driven ILC2 expansion in the intestinal mucosa and their subsequent IL-4 production. Adapted version from the graphical abstract of ref. 107.

Fig 4. T_Reg cell mediated suppression of the adaptive allergic immune response

T_Reg cells regulate allergen-specific Th2 immune responses and B cell IgE production. GITR stimulation of T_Reg cells increase their suppressive functions, leading to their blockade of naïve CD4⁺ T_conv cells conversion into allergen-specific Th2 T cells. T_Reg cells are also able to control B cells and block their IgE production by a direct CTLA-4 and cell contact-dependent mechanism and through the production of immunosuppressive cytokines such as IL-10.

Fig 5. Pathogenic “Th2 cell-like” T_Reg cell reprogramming in food allergy

Food allergy is characterized by a decreased induction of allergen-specific iT_Reg cells at the intestinal mucosa. Induced allergen-specific T_Reg cells in food allergic subjects are prone to acquire a pathogenic skewed “Th2-like” phenotype resulting in increased GATA-3 expression and IL-4 secretion. “Th2 cell-like” iT_Reg cells are dysfunctional and lacking in suppressor function. They are not able to control the T_eff Th2 cell immune response and mast cells expansion, perpetuating in the process the allergic phenotype.

Fig 6. Pathogenic “Th17 cell-like” T_Reg cell reprogramming by the IL-4Rα-Q576R allele

Human IL-4Rα-Q576R is associated with increased asthma severity. Signalling through the IL4Rα-Q576R on iT_Reg cells induces dual activation of STAT6 and STAT3, the latter through an autocrine IL-6 production loop. The IL-6-STAT3 axis promotes pathogenic “Th17 cell-like” T_Reg cell reprogramming resulting in ROR-γt expression and IL-17 secretion by the reprogrammed T_Reg cells.

Fig 7. Microbiota-immune cell interactions shape oral tolerance

Metabolites, such as SFCAs produced by bacterial fermentation of dietary fibers promote the proliferation and de novo induction of iT_Reg cells through FFAR2 (GPR43) receptor and HDAC inhibition. Clostridial bacterial species promote the production of IL-22 by ROR-γt ILC, reinforcing oral tolerance by decreasing gut permeability and oral allergen uptake. Bacteroides Fragilis production of PSA promotes de novo iT_Reg cells generation via TLR2 signalling. MyD88/STAT3-sensing by T_Reg cells enforces oral tolerance by inducing and directing the T_FH - T_FReg and IgA axis. The microbiota also promote the emergence of ROR-γt expressing iT_Reg cells. ROR-γt deficiency in T_Reg cells promotes a Th2 environment and oral allergen sensitization possibly by inducing iT_Reg cell reprograming into “Th2 cell-like” cells expressing GATA-3.