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Regulatory T Cells in Allergy and Asthma* FREE TO VIEW

Mark Larché, PhD
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*From the Division of Clinical Immunology and Allergy, Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.

Correspondence to: Mark Larché, PhD, Canada Research Chair in Allergy and Immune Tolerance, Professor, Department of Medicine, Division of Clinical Immunology and Allergy, Department of Medicine, Faculty of Health Sciences, McMaster University, 1200 Main St W, Hamilton, ON, L8N 3Z5, Canada; e-mail: larche@mcmaster.ca



Chest. 2007;132(3):1007-1014. doi:10.1378/chest.06-2434
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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.

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Asthma, particularly in the young, is a disease associated with an underlying atopic allergic hypersensitivity to one or more allergens. Atopic allergic sensitization is defined by production of IgE against environmental antigens such as proteins from house dust mites (HDMs), grass pollens, animal dander, insects, and foods. Allergic sensitization can lead to a variety of clinical manifestations including asthma, rhinitis, and atopic dermatitis.12 Allergic sensitization to common allergens can be detected in > 25% of the population of some industrialized nations,3and the prevalence of allergic disease has increased markedly within the last 50 years. While atopy and the development of allergic diseases are associated with multiple susceptibility genes, it is clear that there has been no substantial change in the human genome in the last 50 years. It follows, therefore, that environmental factors contribute significantly to the recent increases in disease prevalence. Moreover, similar dramatic trends have been observed in autoimmune diseases such as type I diabetes and multiple sclerosis.4Epidemiologic observations linking prevalence of allergic sensitization with birth order,5 together with numerous subsequent studies investigating the influence of environmental stimuli on the allergic diathesis have lead to the development of the “hygiene hypothesis.” The central canon of the hypothesis is that reductions in exposure to infectious disease and microbial products (through the introduction of vaccines, antibiotics, and improved sanitation) in recent decades has resulted in deficient immune regulation resulting in hypersensitivity in both the T-helper type 1 (Th1) and T-helper type 2 (Th2) compartments.

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 Igε 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 progenitors and prime these cells for activation and chemotaxis. IL-9 is a growth factor for mast cells, and IL-13 has been associated with goblet-cell hyperplasia, mucus hypersecretion, and airway hyperresponsiveness (AHR). TARC and MDC recruit Th2 T cells to sites of allergic inflammation. Whether existing Th2 T cells are required to initiate IgE responses, or whether the presence of allergen-specific IgE is required to generate allergen-specific Th2 responses remain unresolved.

The acute or early phase of allergic inflammation is initiated when the allergen comes into contact with IgE-primed mast cells/basophils. Cross-linking of allergen-specific IgE on the surface of mast cells and basophils leads to the release of mediators including substantial quantities of Th2 cytokines. Mast cell/basophil activation therefore may be sufficient to create the Th2 cytokine milieu that drives Th2 T-cell differentiation and expansion. Expression of IgE receptors on antigen presenting cells (eg, dendritic cells [DCs] and monocytes) allows these cells to capture allergen in a specific fashion through surface-bound IgE.6 The same is true of allergen-specific B cells that express specific membrane Ig. Facilitated antigen presentation of this kind promotes Th2 T-cell differentiation and activation and contributes to dysregulated immune responses to allergen. Thus, allergen-specific IgE amplifies allergen-specific Th2 responses and vice versa. Activation of mast cells/basophils results in the release of mediators such as histamine and leukotrienes that cause bronchoconstriction and airway narrowing through mechanisms that include elements of smooth-muscle constriction and edema.

The late phase of the allergic reaction is characterized by recruitment of activated CD4+ Th2 T cells and eosinophils to sites of allergen exposure. Release of Th2 cytokines (particularly IL-5) from T cells (and mast cells/basophils in the early phase response) leads to the mobilization of bone marrow eosinophils and their progenitors. Local eosinophil recruitment occurs under the influence of chemokines such as eotaxin released from structural cells at the site of allergen exposure. Eosinophils are believed to be important effector cells in the late asthmatic reaction (the late-phase allergic response in the airways of asthmatic individuals), causing epithelial cell damage through release of toxic granule proteins, bronchoconstriction through leukotriene production, and contributing to AHR.7However, clinical studies89 with neutralizing monoclonal antibodies to IL-5 showed no effect on airway function despite marked reduction in numbers of circulating eosinophils. Activation of allergen-specific Th2 T cells with synthetic peptides representing the immunodominant T-cell epitopes of an allergen can lead directly to symptoms of asthma and increased AHR in the absence of the mast cell/basophil component.1011 This relatively recent observation suggests that airway narrowing can occur through both early and late-phase allergic mechanisms, both of which are linked directly and indirectly to allergen-specific T cells and allergen-specific IgE.

It remains unclear precisely why some individuals have allergic disease and others with the same exposure to allergens do not. Moreover, the development of IgE sensitizations to some allergens and not others in atopic individuals implies further levels of complexity. Genes and environment clearly influence sensitization and progression to allergic disease. Recent increases in both the prevalence and incidence of allergic and autoimmune diseases indicate a fundamental defect in immune regulation that is likely to be related to lifestyle and exposure to factors that activate the innate immune system (predominantly microbes and their products). The key to understanding why individuals acquire hypersensitivity to antigens lies in a greater understanding of how healthy individuals regulate the response to self and environmental antigens. In this way it may be possible to define not only the pathogenesis of the disease but also how best to intervene therapeutically.

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.12The 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 individuals in response to allergen.13 However, Th1 responses to allergens would be expected to give rise to inflammatory responses such as delayed-type hypersensitivity reactions, which is not generally the case. Thus, allergic individuals respond to allergen with an inflammatory Th2 response, whereas nonallergic individuals appear to make an immune response that is associated with Th1 cytokines but is noninflammatory.

Studies suggest that active regulation is an essential element in maintaining noninflammatory peripheral tolerance to allergens in healthy individuals. Blood T cells were stimulated with aeroallergens and/or food allergens and subsequently selected on the basis of allergen-induced cytokine production. The profile of allergen-specific interferon (IFN)-γ (Th1 marker), IL-4 (Th2 marker), and IL-10 (antiinflammatory cytokine and marker [Tr1] of a population of regulatory T cells [Treg]) production differed between allergic and nonallergic subjects, with the ratio of cell numbers secreting these three cytokines determining the development of a healthy or allergic immune response. Thus, low Tr1 numbers and high Th2 cell numbers resulted in an allergic response, whereas in nonallergic individuals a mixed Th1/Th2 response was associated with a strong IL-10 response.14Similarly, T-cell clones derived from children persistently allergic to cow milk produced Th2 cytokines (IL-4, IL-13), whereas allergic control subjects without cow milk allergy (but allergic to another food) produced a mixed Th1/Th2 response associated with markedly elevated IL-10 levels.15

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 cells as the season progresses. Many individuals possess allergen-specific IgE, and the first few stings of the season may elicit local allergic reactions. However, reactions to stings disappear rapidly as IL-10 increases. The rise in IL-10 appears to be transient and to require the presence of the allergen because levels return to background shortly after the bee-keeping season.16

Individuals exposed to high levels of cat allergen also appear to be protected from allergic sensitivity through a mechanism that involves the induction of IL-10 and allergen-specific IgG4 rather than IgE.17 The induction of high levels of allergen-specific IgG4 in the relative absence of IgE has been referred to as a modified Th2 response. Interestingly, the relationship between high-dose exposure and the modified Th2 response does not appear to hold true for several other allergens including HDM. Higher doses of HDM exposure are associated with more frequent allergic sensitization. However, it should be appreciated that the relative exposure levels in biological terms may not be equivalent. In other words, high-dose HDM exposure may equate to only moderate cat dander exposure. Were individuals exposed to doses of HDM well in excess of those found in domestic environments, a similar “high-dose tolerance” may be observed.

SIT is associated with the induction of elements of both Th1 and Tr1 responses. Mechanisms of SIT have recently been reviewed elsewhere.18 Early studies identified a relative increase in the IFN-γ:IL-4 ratio in both tissues and peripheral T-cell response following SIT. More recently, IL-10 production has been reported in T cells, B cells, and monocytes/macrophages following SIT. Thus, SIT appears to modify both antigen-presenting cell and T-cell responses through the induction of IL-10 and, in some reports, transforming growth factor (TGF)-β.18 Peripheral blood T cells isolated after SIT were able to suppress allergen-specific proliferation of pretreatment T cells in an IL-10–dependent and TGF-β–dependent fashion because neutralizing antibodies to these cytokines abrogated suppression. Treatment of allergic asthmatic subjects with allergen-derived peptides, representing the major T-cell epitopes, resulted in the induction of IL-10 and of a population of functional CD4+ regulatory T cells capable of downregulating pretreatment T-cell responses to allergen. Changes in allergen-specific antibody isotypes have also been observed following SIT, and these are closely associated with increases in regulatory cytokines, since IL-10 enhances the production of IgG4 (the most prominent isotype induced during SIT) and TGF-β is an isotype switch factor for IgA (less prominently and less frequently observed following SIT).

A distinct Tr1 population expressing high levels of TGF-β has also been identified in the gut and has been labeled T-helper type 3 (Th3).19Th3 cells suppress proinflammatory T-cell responses in the gut and promote IgA isotype switching. TGF-β inhibits proliferation and cytokine secretion in resting T cells but not activated T cells. TGF-β has been shown to induce IL-10 expression in T cells, the latter ameliorating TGF-β–dependent fibrosis.20 IL-10 and TGF-β appear to collaborate in regulating proinflammatory immune responses. Thus, T cells producing IL-10 and/or TGF-β appear to have a regulatory role in the response to allergen in both normal individuals and those exposed to high levels of certain allergens.

IL-10–secreting Tr1-like cells can also be generated with vitamin D3 (1,25(OH)2 VitD3) and corticosteroids such as dexamethasone.21Treatment of allergic and nonallergic individuals with inhaled or systemic glucocorticosteroids resulted in increased expression of IL-10 messenger RNA together with induction of the forkhead (winged helix) transcription factor Forkhead box p3 (Fox p3). Levels of IL-10 and Fox p3 messenger RNA correlated closely.22Preincubation of CD4+CD25+ peripheral blood T cells (Treg) with fluticasone propionate enhanced the ability of these cells to inhibit proliferative responses of CD4+CD25-negative T cells and was associated with increased IL-10 expression. Steroid enhancement of suppression was blocked with an antibody to IL-10.23 The role of IL-10–secreting Tr1s in allergy and asthma has been extensively reviewed elsewhere.24However, IL-10–secreting Tr1s and TGF-β–secreting Th3 cells constitute only two subsets of “adaptive” Tr1s, and there is evidence that other subsets, particularly thymus-derived or “natural” Treg, may also play a role in allergy and asthma. In the context of allergic diseases, Th1 cells may antagonize Th2 responses, and “immune deviation” from a Th2 to a Th1 response may be a legitimate regulatory strategy for the treatment of allergic disease. In addition, natural-killer T cells and γδ T cells have also been shown to have regulatory roles.2526

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 proliferative responses of CD4+CD25-negative T cells.27In addition to high levels of expression of CD25, many phenotypic markers have been associated with natural Treg, including cytotoxic T-lymphocyte–associated antigen 4, neuropilin-1, haem oxygenase-1, notch 3, glucocorticoid-induced tumor necrosis factor receptor, CD38+CD45RB-low, lymphocyte activation gene-3, G protein-coupled receptor 83, and most consistently Fox p3.28Deletion of the Fox p3 gene abrogates suppression by CD4+CD25-high T cells, whereas ectopic expression of the gene in CD25-negative T cells rendered these suppressive.29Mutations in the Fox p3 gene have been described in patients with IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), a syndrome that includes development of elevated IgE responses and atopic dermatitis.30However, IL-10–producing Tr1s do not express Fox p3, indicating that regulation can occur through different pathways.31

The majority of peripheral natural Treg develop in the thymus, but CD4+CD25-high Fox p3+ cells have also been induced in the periphery, in an antigen-specific, TGF-β–dependent fashion, through low-dose antigen (peptide) exposure.32Thymic differentiation of these cells occurs through positive selection events facilitated by medullary epithelial cells (particularly within Hassall corpuscles) and thymic stromal lymphopoietin (TSLP)-activated medullary DCs.33Interestingly, with respect to allergic disease, TSLP-activated DCs produce large quantities of the Th2 chemokines TARC and MDC. Unlike many DC subsets, they produce little in the way of proinflammatory Th1 cytokines such as IL-12 and tumor necrosis factor-α. In the thymus, TSLP-activated DCs induced expression of Fox p3 and CD25 in thymocytes. Furthermore, TSLP-activated DCs induced strong proliferative responses (in the absence of Th1 or Th2 cytokines) and regulatory function in these cells. However, in the periphery, TSLP-activated DCs strongly activated T cells but induced differentiation of Fox p3-negative Th2 T cells rather than Treg (Fig 1 ).34 Interestingly, TSLP is highly expressed by keratinocytes from patients with atopic dermatitis and is associated with the induction of strong Th2 responses and production of IL-4, IL-5, IL-13, and tumor necrosis factor-α, while downregulating expression of IL-10 and IFN-γ.35Numbers of CD4+CD25-high Fox p3+ Treg are reduced in the skin of patients with atopic dermatitis36 despite apparently normal numbers of these cells in the peripheral blood.37

Similar mechanisms appear to be associated with the development of natural CD4+CD25-high Fox p3+ Treg in the thymus and Th2 T cells in the periphery. Understanding the different signals that lead to these divergent cell fates may be key to understanding the failure of peripheral regulation in allergic disease. Naïve T cells activated by TSLP-activated DCs, or functionally immature DCs, may lead to Th2 differentiation in a low–TGF-β, high–IL-2 microenvironment in the skin (for example through bacterial superantigen-dependent T-cell activation and IL-2 production in atopic dermatitis), whereas the relative absence of IL-2 (and/or other growth factors) and the presence of TGF-β may lead to preferential differentiation of Treg.

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 season, suggesting that increased allergen dose in vivo may provide a strong enough stimulus to override Treg-mediated suppression.

Other similar studies39 have also found evidence of defective regulation but with some caveats. For example, CD4+CD25+ T-cell function from birch pollen-allergic subjects and nonallergic control subjects was compared in and out of season. While both groups had equivalent suppression of allergen-induced proliferation and similar suppression of IFN-γ, suppression of Th2 responses appeared to be compromised in allergic subjects, as both CD4+CD25+ and CD4+CD25-negative T cells made IL-5 and IL-13 to birch pollen.,39The findings are consistent with the observation40 that Th2 thymocyte clones were more resistant to regulation by either CD4+CD25+ or CD8+CD25+ regulatory human thymocytes than were Th1 thymocyte clones.

A third study41 concluded that in the majority of allergic individuals (predominantly rhinitics sensitive to grass pollen or birch in this study), there are no defects in the ability of CD4+CD25+ T cells to regulate proliferative and cytokine responses. However, a subgroup of allergic subjects who produced high levels of IL-4 and IL-10 were unable to regulate effectively.,41Further related experiments demonstrated that both dose and type of allergen appear to have important effects on the ability of CD4+CD25+ T cells to suppress responses.42 In grass pollen-allergic individuals, stimulation of T cells with high concentrations of allergen resulted in a failure in the ability of CD4+CD25+ T cells to suppress proliferative responses of CD4+CD25-negative T cells. Moreover, CD4+CD25+ T cells lost their characteristic anergic phenotype and were able to proliferate. Interestingly, the ability of CD4+CD25+ T cells to suppress Th1 and Th2 cytokine production was retained at high allergen dose, reiterating the differential regulation of cytokine and proliferation responses identified in other studies.,41In the same study,42 CD4+CD25+ T cells from wasp venom-allergic individuals were cultured with a range of allergen doses. In contrast to results with grass pollen, CD4+CD25+ T cells from these subjects were unable to suppress either proliferative or cytokine responses. In fact at higher concentrations, stronger proliferative responses were observed as the CD4+CD25+ T cells themselves proliferated. Some of the same subjects were also grass pollen allergic; in these individuals, the ability to suppress grass pollen responses was retained. Finally, CD4+CD25+ T cells from nonvenom-allergic individuals were able to suppress proliferation and cytokine responses but only at low allergen dose. Thus, allergens vary in their ability to override CD4+CD25+ Treg suppression, both by virtue of dose and intrinsic allergen-specific properties that remain to be identified.

There is a dearth of data relating to the status of Tr1s in individuals with asthma. However, numbers of IL-10–secreting CD4+ T cells have been reported to be reduced in severe unstable asthma, as compared to severe-stable asthma and mild asthma.43 Peripheral blood T cells were stimulated with anti-CD3 and anti-CD28 prior to intracellular staining for IL-10 analyzed by flow cytometry. The numbers of subjects were small in this study,43 and no differences were seen between the groups in sputum and blood eosinophilia or exhaled nitric oxide. The dose of corticosteroids used to treat the severe asthmatics did not influence IL-10 production. However, larger studies are required in order to fully determine the extent of the deficiency in T-cell regulation in asthma.

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 development of IL-10–secreting Tr1-like regulatory cells. TGF-β is crucial in the development of CD4+CD25+ Treg and induces expression of the master regulatory transcription factor Fox p3. While TGF-β has profibrotic characteristics that may compromise its use as a therapeutic, a combination of TGF-β and IL-10 may enhance regulatory function while reducing associated fibrosis. IL-6 is an archetypal proinflammatory cytokine that is able to enhance allergic airway disease and suppress the generation of Treg. Blockade of the IL-6 pathway has already been achieved in other clinical disorders and may prompt studies to evaluate this form of intervention in asthma.44 TSLP induces expression of the Th2 chemokines TARC and MDC, which drive recruitment of Th2 T cells to sites of allergic inflammation. Inhibitors of CC chemokine receptor 4, the receptor for these molecules, are already being developed for the treatment of asthma.

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 and may differ for the various regulatory populations. SIT appears to induce allergen-specific regulation that contributes to the efficacy of the treatment. Corticosteroids and other compounds such as vitamin D3 can induce regulatory characteristics in T cells through induction of IL-10. Improved understanding of regulatory mechanisms in development of allergic sensitization and their manipulation with immunotherapy and pharmacotherapy holds the promise of vaccination and treatment strategies for asthma and other allergic diseases.

Abbreviations: AHR = airway hyperresponsiveness; DC = dendritic cell; Fox p3 = Forkhead box p3; HDM = house dust mite; IFN = interferon; IL = interleukin; MDC = monocyte-derived chemokine; SIT = specific allergen immunotherapy; TARC = thymus and activation regulated chemokine; TGF = transforming growth factor; Th1 = T-helper type 1; Th2 = T-helper type 2; Th3 = T-helper type 3; Treg = regulatory T cells; Tr1 = antiinflammatory cytokine and marker; TSLP = thymic stromal lymphopoietin

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).

Figure Jump LinkFigure 1. TSLP drives development of Treg and Th2 cells. TSLP is secreted by epithelial cells in the periphery or in Hassall corpuscles in the thymus. TSLP-activated DCs in the thymus induce Treg (CD4+CD25+ Foxp3+). TGF-β may contribute to conversion of developing thymocytes into Treg by slowing down T-cell proliferation. TSLP-activated DCs in the periphery induce Th2 T cells. IL-2 may contribute to the development of Th2 rather than Treg by enhancing proliferation. TSLP-activated DCs produce TARC and MDC that recruit T cells expressing CC chemokine receptor 4, which may include both Treg and Th2 cells.Grahic Jump Location
Figure Jump LinkFigure 2. Treg inhibit the effector phase of the allergic response. Under the appropriate conditions, antigen-presenting cells present allergen in the form of short peptides bound to major histocompatibility complex molecules, to T cells resulting in Th2 activation and differentiation. Thymus-derived CD4+CD25-high Foxp3+ natural Treg inhibit this process through cell contact-dependent mechanisms. Adaptive Treg such as Tr1 and Th3 cells are generated in the periphery and are generally allergen/antigen specific. These cells are also capable of inhibiting the development of effector Th2 responses through both cytokine secretion (TGF-β and/or IL-10) and other less well-defined mechanisms. The function of CD4+CD25+ T cells is thought to be compromised in allergic individuals. High-dose tolerance to bee venom or to cat allergen exposure is associated with the development of IL-10–secreting Tr1-like cells that prevent expression of the allergic response. Individuals treated with allergen immunotherapy have adaptive allergen-specific Tr1s secreting both IL-10 and TGF-β.Grahic Jump Location
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Ou, LS, Goleva, E, Hall, C, et al T regulatory cells in atopic dermatitis and subversion of their activity by superantigens.J Allergy Clin Immunol2004;113,756-763. [PubMed]
 
Ling, EM, Smith, T, Nguyen, XD, et al Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease.Lancet2004;363,608-615. [PubMed]
 
Grindebacke, H, Wing, K, Andersson, AC, et al Defective suppression of Th2 cytokines by CD4CD25 regulatory T cells in birch allergics during birch pollen season.Clin Exp Allergy2004;34,1364-1372. [PubMed]
 
Cosmi, L, Liotta, F, Angeli, R, et al Th2 cells are less susceptible than Th1 cells to the suppressive activity of CD25+ regulatory thymocytes because of their responsiveness to different cytokines.Blood2004;103,3117-3121. [PubMed]
 
Bellinghausen, I, Klostermann, B, Knop, J, et al Human CD4+CD25+ T cells derived from the majority of atopic donors are able to suppress TH1 and TH2 cytokine production.J Allergy Clin Immunol2003;111,862-868. [PubMed]
 
Bellinghausen, I, Konig, B, Bottcher, I, et al Regulatory activity of human CD4 CD25 T cells depends on allergen concentration, type of allergen and atopy status of the donor.Immunology2005;116,103-111. [PubMed]
 
Matsumoto, K, Inoue, H, Fukuyama, S, et al Decrease of interleukin-10-producing T cells in the peripheral blood of severe unstable atopic asthmatics.Int Arch Allergy Immunol2004;134,295-302. [PubMed]
 
Kunitomi, A, Konaka, Y, Yagita, M, et al Humanized anti-interleukin 6 receptor antibody induced long-term remission in a patient with life-threatening refractory autoimmune hemolytic anemia.Int J Hematol2004;80,246-249. [PubMed]
 

Figures

Figure Jump LinkFigure 1. TSLP drives development of Treg and Th2 cells. TSLP is secreted by epithelial cells in the periphery or in Hassall corpuscles in the thymus. TSLP-activated DCs in the thymus induce Treg (CD4+CD25+ Foxp3+). TGF-β may contribute to conversion of developing thymocytes into Treg by slowing down T-cell proliferation. TSLP-activated DCs in the periphery induce Th2 T cells. IL-2 may contribute to the development of Th2 rather than Treg by enhancing proliferation. TSLP-activated DCs produce TARC and MDC that recruit T cells expressing CC chemokine receptor 4, which may include both Treg and Th2 cells.Grahic Jump Location
Figure Jump LinkFigure 2. Treg inhibit the effector phase of the allergic response. Under the appropriate conditions, antigen-presenting cells present allergen in the form of short peptides bound to major histocompatibility complex molecules, to T cells resulting in Th2 activation and differentiation. Thymus-derived CD4+CD25-high Foxp3+ natural Treg inhibit this process through cell contact-dependent mechanisms. Adaptive Treg such as Tr1 and Th3 cells are generated in the periphery and are generally allergen/antigen specific. These cells are also capable of inhibiting the development of effector Th2 responses through both cytokine secretion (TGF-β and/or IL-10) and other less well-defined mechanisms. The function of CD4+CD25+ T cells is thought to be compromised in allergic individuals. High-dose tolerance to bee venom or to cat allergen exposure is associated with the development of IL-10–secreting Tr1-like cells that prevent expression of the allergic response. Individuals treated with allergen immunotherapy have adaptive allergen-specific Tr1s secreting both IL-10 and TGF-β.Grahic Jump Location

Tables

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Ling, EM, Smith, T, Nguyen, XD, et al Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease.Lancet2004;363,608-615. [PubMed]
 
Grindebacke, H, Wing, K, Andersson, AC, et al Defective suppression of Th2 cytokines by CD4CD25 regulatory T cells in birch allergics during birch pollen season.Clin Exp Allergy2004;34,1364-1372. [PubMed]
 
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Bellinghausen, I, Klostermann, B, Knop, J, et al Human CD4+CD25+ T cells derived from the majority of atopic donors are able to suppress TH1 and TH2 cytokine production.J Allergy Clin Immunol2003;111,862-868. [PubMed]
 
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