The Role of IL-10 and TGF-β in the Differentiation and Effector Function of T Regulatory Cells

Levings, Megan K.; Bacchetta, Rosa; Schulz, Ute; Roncarolo, Maria Grazia

doi:10.1159/000067596

Cited by 366 publications

(254 citation statements)

References 96 publications

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“…This capacity of heatdenatured allergens to enhance the immunogenicity of allergens and to shift the cellular response towards Th1 would ideally fulfil the consensus requirements for successful SIT [1]. Although the frequencies of regulatory CD4-positive T cells and the levels of secreted IL-10 have been shown to increase in PBMC from desensitised patients [33][34][35][36], the fact that clinical symptoms develop within seconds of a bee sting suggests that neutralising antibodies play an important role in protection, unless there exist regulatory T cells that exert a more direct effect on mast cells and basophils. The importance of antibodies is further underlined by the fact that short immunotherapy with heat-denatured allergens, but not with native allergens, protected allergic mice against naturally induced anaphylaxis (Fig.…”

Section: Discussionmentioning

confidence: 99%

Heat denaturation, a simple method to improve the immunotherapeutic potential of allergens

et al. 2005

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Allergen-specific immunotherapy (SIT) leads to a long-term amelioration of IgE-and Th2-mediated allergic diseases. However, SIT efficiency is low, with years of treatment along with frequent allergic side effects. The goal of this study was to reduce the side effects by destroying IgE-binding epitopes, i.e. by heat-denaturation, while preserving the therapeutic effect. Mice were immunised with bee venom, birch pollen, grass pollen or cat hair allergens, or with ovalbumin. Heat-denatured allergens bound less IgE but enhanced Th1-dependent IgG2a production as measured by ELISA. The strong IgG2a antibody responses also prevented allergic anaphylaxis in mice, as measured by body temperature drop after a challenge with a high allergen dose. We found that optimal heat-denaturation of allergens left a small proportion in the native conformation to sufficiently stimulate B cells, while non-B cell-mediated effects were probably amplified. The enhanced immunogenicity of heat-denatured allergens is likely explained by enhanced antigen presentation to T cells due to the particulate nature of heat-denatured proteins. This enables Th1 skewing of the immune response with strong production of IgG2a in mice. Therefore, heat-denaturation represents probably the simplest way to enhance the efficiency of SIT while reducing its side effects. IntroductionIgE-mediated type I hypersensitivity is characterised by prominent activity of mast cells, eosinophils, T helper type 2 (Th2) cells and cytokine actions. Allergenspecific immunotherapy (SIT) leads to long-term amelioration of allergic symptoms and is therefore recommended as a first-line therapy for allergies [1]. During SIT, gradually increasing allergen doses are subcutaneously administered until a maintenance dose is reached, and then treatment continues for 3-5 years. Such lengthy treatment, requiring 30-80 allergen injections, is very costly [2]. Also, SIT frequently causes adverse events due to the interaction of specific IgE with the injected allergen. These adverse events frequently include a local reaction at the site of allergen injection, but also life-threatening systemic reactions such as asthma and anaphylaxis. This is why the administered allergen doses must be kept relatively low, which unfortunately favours Th2 immune responses in contrast to higher doses [3][4][5].Several strategies have been developed to tackle the problems of SIT, i.e. to reduce its side effects and to enhance its immunogenicity. One strategy is to replace the currently used aluminium salts, which have Th2-polarizing properties, with novel adjuvants such as Tolllike receptor ligands [6,7] that trigger Th1 responses. Another strategy is to increase safety and tolerability of SIT by injecting the allergen in a form that is not recognised by IgE, such as naked DNA vaccines Heat-denaturation is well known to reduce the reactogenicity of allergens with IgE, as cooked foods are usually well or better tolerated by allergic individuals [24][25][26]. In this study, we tested whether this very simple strate...

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Section: Discussionmentioning

confidence: 99%

Heat denaturation, a simple method to improve the immunotherapeutic potential of allergens

et al. 2005

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“…CD4 and CD25 therefore do not qualify as a descriptor of suppressive T-cells, and additional markers are required that could include CTLA4. In vitro generation of suppressive T-cells has been a major challenge, but seems to be possible with help of for instance IL-10 [43,47]. The only example of T-cells with suppressive function in Type 1 diabetes stems from an as yet ill-defined lymphocyte subset that expresses CD45RA.…”

Section: Role Of T-cells In Protection From Beta-cell Destructionmentioning

confidence: 99%

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

2003

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“…Th3 and Tr1 cells down-regulate responses, primarily at mucosal sites, to non-self proteins, by the secretion of suppressive cytokines like IL-10 and TGF-b [14,20].…”

Section: Introductionmentioning

confidence: 99%

Impaired regulatory T cell function in germ‐free mice

et al. 2006

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Regulatory T cells (Treg) are crucial for the maintenance of tolerance to auto-antigens and harmless exogenous antigens. Here, we studied the role of the commensal microbiota for the development and function of Treg. CD4 + CD25 + T cells were obtained from peripheral lymph nodes (PLN) and mesenteric lymph nodes (MLN) of germ-free (GF) and conventional (conv) NMRI mice and tested for phenotype and functional suppressive capacity. CD4 + CD25 + T cells from GF mice showed a lower relative gene expression of fork head box p3 gene (Foxp3) and were not as potent suppressors in vitro as CD4 + CD25 + T cells from conv animals. Intracellular staining for Foxp3 and CTLA-4 revealed proportional and regional differences in putative Treg subsets between conv and GF mice. Fewer of the CD4 + CD25 + T cells in GF MLN expressed Foxp3 and CTLA-4, while the expression of these markers was similar amongst the CD4 + CD25 + T cells in PLN of conv and GF mice. The largest difference between conv and GF Treg was observed in the liver draining celiac lymph node, where GF mice had fewer putative Treg as compared to conv mice. We propose that the presence of a microbial flora favors the development of a fully functional Treg population. IntroductionRegulatory T cells down-regulate unwanted and exaggerated immune reactions to auto-antigens as well as innocuous environmental antigens. Different subsets of Treg have been defined. Natural CD4 + CD25 + Treg are positively selected for tissue-specific self-Ag in the thymus and exert their suppressive effect by cell-cell contact-dependent mechanisms [1]. Deficiency in the Treg population or neonatal thymectomy result in multiorgan autoimmune diseases [2][3][4][5][6][7][8]. Treg are characterized by a dense surface expression of CD25 (the a-chain of the IL-2-receptor), glucocorticoidinduced TNF receptor (GITR) and intracellular CTLA-4, however, these markers may be present on activated T cells. CD4 + CD25 + Tregs appear to be unique in transcribing the fork head box p3 gene (Foxp3) transcription factor [6,9], which enable their identification either with PCR are or newly developed mAb to the Foxp3 protein. Lack of a functional Foxp3 gene result in the severe autoimmune syndrome IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), characterized by organ-specific autoimmunity, colitis and high IgE levels [10,11]. Mice with spontaneous or induced mutations in the Foxp3 gene that impair Foxp3 expression fail to develop CD4 + CD25 + Treg and exhibit a syndrome similar to IPEX [5,6].Other subsets of Treg are induced in the periphery and are referred to as Th3 [12][13][14] and Tr1 cells [15][16][17][18][19] can also generate Treg. This implies that the state of the APC and the local cytokine milieu, e.g. in the normal gut where both IL-10 and TGF-b are abundant, can determine the outcome of an immune reaction, and that Treg are induced under these circumstances.The aim of this study was to investigate the phenotype and functionality of CD4 + CD25 + Treg from germ-free (GF) ...

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The Role of IL-10 and TGF-β in the Differentiation and Effector Function of T Regulatory Cells

Cited by 366 publications

References 96 publications

Heat denaturation, a simple method to improve the immunotherapeutic potential of allergens

Heat denaturation, a simple method to improve the immunotherapeutic potential of allergens

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

Impaired regulatory T cell function in germ‐free mice

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