Regulatory T Cells in Allergy and Asthma

doi:10.1378/chest.06-2434

Chest

Volume 132, Issue 3, September 2007, Pages 1007-1014

https://doi.org/10.1378/chest.06-2434 Get rights and content

Allergic diseases including asthma have risen considerably in prevalence in the last 50 years. A concomitant rise in autoimmune disease suggests a defect in immunoregulation, rather than a reduction in T-helper type 1 immunity. Immune responses to innocuous environmental antigens in health are characterized by dominant regulation through the production of interleukin-10 and transforming growth factor-β. Recent studies suggest that diverse populations of regulatory T cells (Treg) play an important role in regulating T-helper type 2 (Th2) responses to allergens, maintaining functional tolerance. Regulatory responses appear to be compromised in allergic individuals but may be reconstituted to some extent with specific allergen immunotherapy. In experimental models, Treg can suppress Th2 responses to allergen, airway eosinophilia, mucous hypersecretion, and airway hyperresponsiveness. Further studies are required to precisely define the mechanisms of development and action of these cells, and to identify and evaluate novel targets for the treatment of allergic diseases.

Section snippets

The Allergic Immune Response

In addition to the humoral IgE component, allergic immune responses are characterized by Th2 T cells specific for the allergen, and the production of Th2 cytokines (interleukin [IL]-4, IL-5, IL-9, IL-13, and others) and Th2-associated chemokines (thymus and activation-regulated chemokine [TARC], monocyte-derived chemokine [MDC]). IL-4 and IL-13 act as Igɛ heavy chain isotype switch factors leading to the production of IgE. IL-4, IL-5, and IL-9 enhance the survival of eosinophils and their

Allergen-Specific Responses in Nonallergic Individuals

Cytokine production by allergen-specific T cells is crucial in establishing and maintaining the tolerant or inflammatory context of allergen recognition. Production of Th2 cytokines is associated with allergic diseases including asthma.¹² The nonallergic phenotype has historically been associated either with a failure to recognize the allergen (immunologic ignorance) or the expression of a “protective” Th1 cytokine profile. Indeed, Th1 cytokine profiles have been reported in nonallergic

Tr1 and T-Helper Type 3

Further examples of a role for IL-10–producing Tr1s in the maintenance of tolerance to allergens can be found in three groups of individuals exposed to relatively high doses of allergen: bee keepers, individuals naturally exposed to high ambient concentrations of cat dander, and allergic patients undergoing specific allergen immunotherapy (SIT). Bee keepers stung repeatedly during the bee-keeping season demonstrate a marked increase in allergen-specific IL-10 secretion from peripheral blood T

Natural (Thymus-Derived) Treg (CD4+CD25^hi Fox p3⁺)

The T-cell population bearing the CD4+CD25+ phenotype houses both activated T-helper cells and Treg. A number of molecules have been identified that make it possible to differentiate these two populations both phenotypically and functionally. Natural Treg (CD4+CD25-high Fox p3⁺) constitute 5 to 10% of the peripheral T-cell pool in humans and mice. They do not proliferate in response to either polyclonal anti-CD3 stimulation or antigenic stimulation and, furthermore, they can inhibit the

Defective Regulation in Allergic Diseases and Asthma

Compromised regulation may provide an explanation for hyperreactivity to allergens and autoantigens. A number of studies have investigated the possibility that allergen-specific Treg function is defective in individuals with allergic diseases (Fig 2). CD4⁺CD25⁺ T cells from grass pollen-allergic individuals were less able to suppress proliferative responses and IL-5 production by CD4⁺CD25-negative T cells.³⁸ Moreover, suppression by CD4⁺CD25⁺ T cells was further compromised during the pollen

Targets for Intervention

Based on the studies reported here, it is clear that targeting of a number of cell-surface molecules and soluble mediators may be beneficial in asthma. DCs activated with TSLP are involved in the generation of Tr1s in the thymus, but Th2 cells in the periphery. Improved understanding of the signals that drive this divergent pathway may identify novel molecules as targets for intervention either alone, or in combination with TSLP. Signaling of tolerogenic DCs to naïve T cells can lead to the

Conclusions

In conclusion, CD4⁺CD25⁺ T cells and IL-10–producing Tr1s have the capacity to suppress Th2 responses to allergen. Particular combinations of DCs and cytokines induce Treg development. Immune responses to allergens in healthy individuals include a dominant regulatory element. There is evidence that the function of Treg may be defective in those with allergic diseases including rhinitis, atopic dermatitis, and asthma. The exact mechanisms of suppression employed by some Treg remain controversial

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Regulatory T (Treg) cells maintain immune tolerance to allergens at the environmental interfaces in the airways, skin and gut, marshalling in the process distinct immune regulatory circuits operative in the respective tissues. Treg cells are coordinately mobilized with allergic effector mechanisms in the context of a tissue-protective allergic inflammatory response against parasites, toxins and potentially harmful allergens, serving to both limit the inflammation and promote local tissue repair. Allergic diseases are associated with subverted Treg cell responses whereby a chronic allergic inflammatory environment can skew Treg cells toward pathogenic phenotypes that both perpetuate and aggravate disease. Interruption of Treg cell subversion in chronic allergic inflammatory conditions may thus provide novel therapeutic strategies by re-establishing effective immune regulation.
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In brief, we supposed that miRNAs/HO-1 could mediate allergy through oxidative stress pathways, transcription factors and immune cell functions such as mast cell maturation, chemokine expression in T cell and dendritic cell degranulation. Although the detailed mechanism needs further research, this review may reveal the potential application of miRNAs and HO-1 in genetic therapies of allergic disease and provide new biomarkers.
This article examines the latest knowledge and studies on the protective roles and mechanisms of miRNA-HO-1 in allergy. Moreover, via bioinformatics analysis of GEO dataset, it was demonstrated that miRNAs (e.g. miR-205, miR-203, and miR-483-5p) could regulate allergy process through HO-1.
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Both obesity and low vitamin D levels have been associated with allergic asthma (AA) severity. In the present study, severity of AA was associated with obesity but to the in vitro IgE production. In those patients, higher levels of IL-5, IL-6 and IL-17 were quantified in CD4⁺ T-cell cultures as compared with patients with mild and moderate AA. In addition, the lowest IL-10 levels were detected in the cell cultures from patients with a worse prognosis. Interestingly, the occurrence of AA elevates the plasma levels of leptin, and this adipokine was positively correlated with the release of IL-5, IL-6 and IL-17, but inversely correlated with IL-10 production, by CD4⁺ T-cells from patients. In AA-derived CD4⁺ T-cell cultures, 1,25(OH)2D3 was less efficient at inhibiting IL-5, IL-6 and IL-17 production, and up regulating IL-10 release, as those from healthy subjects. Interestingly, the in vitro immunomodulatory effects of vitamin D were inversely correlated with serum leptin levels. In summary, our findings suggested that obesity, probably due to the overproduction of leptin, negatively impacts AA as it favors imbalance between Th2/Th17 and regulatory phenotypes. The deleterious effects of leptin may also be due to its ability to counter-regulate the immunosuppressive effects of vitamin D.
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Citation Excerpt :
Foremost amongst these are thymus-derived naturally occurring CD4+CD25+FOXP3+ regulatory T cells (nTreg), which are widely regarded as the primary forces in maintaining peripheral immune tolerance [6]. Studies show that FoxP3+ natural Tregs are engaged in the prevention of immunopathological, auto-immune, and allergic diseases, and that their qualitative and/or quantitative defects can be a cause of these diseases [7,8]. FoxP3+Treg cells have long been considered an immunosuppressive population.
Human regulatory T cells (Tregs) are a heterogeneous population which consists of three distinct subpopulations: CD25⁺CD45RA⁺ resting Treg (rTreg) cells; CD25^hiCD45RA⁻ activated Treg (aTreg) cells, which are both suppressive; and CD25⁺CD45RA⁻ cytokine-secreting T cells with pro-inflammatory capacity.
We investigated variation in peripheral Treg subpopulations of asthma and explored their potential roles in asthma inflammation.
Twenty-eight mild asthma patients, 26 moderate asthma patients, 18 severe asthma patients, and 36 healthy controls were recruited for a cross-sectional study. Phenotyping of peripheral CD4⁺ Tregs was performed based on flow cytometry results.
The proportions of rTreg and aTreg cells among CD4⁺ T cells were higher in mild and moderate asthma patients than in healthy controls. All three groups of asthmatics had a higher proportion of pro-inflammatory Tregs than healthy controls, and these increased with asthma severity. The proportion of IL-17-producing Foxp3⁺ cells and IFN-ɤ-producing Foxp3⁺ cells strongly correlated with T helper 17 (Th17) cells (r = 0.66, p < 0.001) and Th1 cells (r = 0.48, p < 0.001). The pro-inflammatory Treg subpopulation was correlated with the severity of asthma and may be insensitive to corticosteroids.
Our data suggest that pro-inflammatory Treg subpopulations may be relevant to the plasticity of Th17 and Th1 differentiation and play an important role in the pathogenesis of asthma.
18β-Glycyrrhetinic acid, the major bioactive component of Glycyrrhizae Radix, attenuates airway inflammation by modulating Th2 cytokines, GATA-3, STAT6, and Foxp3 transcription factors in an asthmatic mouse model
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The results showed that both pre- and posttreated FIP-fve groups had significantly reduced airway hyperresponsiveness compared with the PC group after methacholine challenge. In addition, a significantly decreased level of HDM-specific immunoglobulin E in serum and decreased production of Th2 cytokines in bronchoalveolar lavage fluid and serum were observed in these two FIP-fve fed groups. Moreover, more decreased amounts of infiltrating inflammatory cells were present in the lungs of FIP-fve fed groups than those of the PC group.
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The author acts as a consultant to, and holds equity in Circassia Holdings Ltd., a company developing peptide-based immunotherapy for allergic and autoimmune diseases.

The author is currently funded by the Canada Research Chairs Program and the Canadian Foundation for Innovation. The author's research has been funded by Asthma UK and the Medical Research Council (United Kingdom).

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Chest

TRANSLATING BASIC RESEARCH INTO CLINICAL PRACTICERegulatory T Cells in Allergy and Asthma

Section snippets

The Allergic Immune Response

Allergen-Specific Responses in Nonallergic Individuals

Tr1 and T-Helper Type 3

Natural (Thymus-Derived) Treg (CD4+CD25hi Fox p3+)

Defective Regulation in Allergic Diseases and Asthma

Targets for Intervention

Conclusions

J Allergy Clin Immunol

Immunol Today

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

Blood

J Allergy Clin Immunol

Allergy and allergic diseases: first of two parts

N Engl J Med

Allergy and allergic diseases: second of two parts

N Engl J Med

The effect of infections on susceptibility to autoimmune and allergic diseases

N Engl J Med

Hay fever, hygiene, and household size

BMJ

Allergy and allergic diseases: first of two parts

N Engl J Med

Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study

Am J Respir Crit Care Med

Late asthmatic reactions induced by inhalation of allergen-derived T cell peptides

Am J Respir Crit Care Med

Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions

J Exp Med

Evidence for compartmentalization of functional subsets of CD2+ T lymphocytes in atopic patients

J Immunol

Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells

J Exp Med

TRANSLATING BASIC RESEARCH INTO CLINICAL PRACTICE
Regulatory T Cells in Allergy and Asthma

Natural (Thymus-Derived) Treg (CD4+CD25^hi Fox p3⁺)