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• W1995797755 abstract "The importance of T cells in regulating antibody production is well established and we now understand a great deal about the way that allergen-specific T cells interact with allergen-specific B-cells leading to the production of IgE [ 1, 2]. Separately, there is a convincing body of evidence showing that asthma is associated with increased numbers of activated T cells in the bronchial mucosa and in bronchoalveolar lavage (BAL) [ 3, 4]. As well as the IL-4 which is implicated in isotype switching towards IgE, T-cells produce a number of other cytokines which have been implicated in the pathogenesis of airways inflammation. In particular, IL-5 is a critical cytokine for the differentiation, activation and survival of eosinophils [ 5]. IL-5 protein and mRNA expression are increased in asthmatic airways [ 6, 7], while inhalation of recombinant human IL-5 induces sputum eosinophilia and increased non-specific bronchial reactivity in asthmatics [ 8]. The T-cell cytokine interferon-γ (IFN-γ) opposes the actions of IL-4 on T-cells and B cells [ 9] but has pro-inflammatory actions on macrophages, eosinophils, endothelial cells and other components of the airways [ 101112]. While IFN-γ was originally considered to be an anti-allergic cytokine and it was thought that allergy and asthma might be due to a reduction in IFN-γ production, in fact BAL T cells from patients with asthma have an increased capacity for IFN-γ production [ 13] and treatment with subcutaneous or inhaled recombinant IFN-γ has no beneficial effect on steroid-dependent asthma, although it does reduce blood eosinophilia [ 14]. When considering the role of T lymphocytes in asthma, one of the key issues to be remembered is that T cells have very precise antigen recognition requirements. T lymphocytes recognize antigens through a receptor structure, the T-cell receptor (TCR) which is strictly associated with the γ, δ, ɛ and ζ chains of the CD3 molecule which serves as a signal transducer to the T-cell interior. TCRs are heterodimers comprising either α/β or γ/δ chains each encoded (just like immunoglobulins on B-cells) by variable (V), diversity (D), joining (J) and constant (C) gene segments that undergo somatic rearrangement during T-cell development [ 15]. The CD3 components show no amino acid variability in different T cells and thus do not influence the diversity associated with TCRs. The Vα and Vβ gene segments can be clustered into families based upon nucleotide sequence similarities and their protein products can be identified by family specific monoclonal antibodies. To date 30 Vα and 24 Vβ families have been identified in man. The diversity created by the random pairing of Vα and Vβ genes thus allows 720 possible combinations. This is further augmented by junctional flexibility (the imprecise joinings of the gene segments) and N-region diversity (the addition of non-genomic nucleotides at junction points) which occur during the somatic rearrangement process. The hypervariability of the V(D)J joining process leads to an almost innumerable range of possible amino acid sequences in the antigen-recognition site and hence the ability to recognize an almost infinite variety of antigens [ 15]. The TCR α and β chains each have three points of contact with the MHC molecule–peptide. These are termed complementarity determining regions (CDR). The CDR1 and CDR2 regions bind to polymorphic framework regions of the MHC molecule, while the CDR3 region constitutes the antigen-combining site. Broadly speaking, the CDR1 and CDR2 regions are formed from the framework regions of the V segment, while the CDR3 s are formed from the Vα–Jα and Vβ–Dβ–Jβ junction regions ( Fig. 1). and CDR2 regions contact the MHC molecule while the CDR3 regions contact the antigen fragment contained in the groove of the MHC molecule. Note that the CDR3 regions contain the areas that experience maximum diversity in the process of somatic recombination which occurs to assemble the unique TCR expressed by each T cell. The T-cell response of an individual to antigens depends on the available T-cell repertoire, which is known to be influenced by the HLA haplotype of the individual, but is also affected by environmental factors such as exposure to antigens or superantigens [ 16]. With antigens that have a very restricted range of T-cell epitopes there may be an extremely restricted repertoire of TCRs which can recognize that antigen. In the human context, analysis of TCR family usage at sites of inflammation such as the airways, can yield insight into the forces that drive the formation of the T-cell repertoire [ 17]. In peripheral blood the TCR repertoire within any given Vβ family is virtually always polyclonal, but clonal populations can be identified in airways T-cell populations, both in health and disease [ 1819202122]. This type of analysis has allowed us to detect clonal expansion within the airways in sarcoidosis [ 18, 19], in extrinsic allergic alveolitis [ 19, 20] and in asthma [ 21, 22], and makes it possible to assess whether the T-cell activation seen in asthmatic airways is a specific or a non-specific event. Interestingly, it seems that allergen challenge of human airways can lead to the appearance of new, clonal T-cell subpopulations which are not present at baseline and are not seen after sham challenge with saline [ 22]. In this issue of the journal, Hofstra and colleagues [ 23] have used a murine model of allergic asthma [ 24, 25] to investigate the role of allergen-specific Vβ8 T-cells in the regulation of antigen-specific IgE, airways hyperresponsiveness and cellular infiltration in the BAL and in the airways, both during the sensitization process and at the time of allergen challenge. In BALB/c mice the immune response to OVA is mediated via T cells that bear a limited set of TCRs, predominantly Vβ8 and less frequently Vβ2 and Vβ14 T-cell receptors [ 26, 27]. The Vβ8 T cells efficiently recognize the peptide OVA323–329, which represents a major epitope of OVA for both B and T lymphocytes, whereas it is unclear at present which epitope is recognized by the OVA-specific Vβ2 or Vβ14 T cells. In this model, in vitro IgE production by B lymphocytes is stimulated only in the presence of Vβ8 T cells, with an associated increase in the number of IgE-secreting B cells whereas Vβ2 OVA-specific T cells not only lack the capacity to stimulate IgE production but, if anything, they seem to inhibit IgE production [ 26]. Moreover passive transfer of activated Vβ8 T cells to naive recipient mice induced antigen-specific IgE production in vivo [ 27]. Intriguingly, Hofstra et al. found that treatment of BALB/c mice with antibodies to Vβ8 prior to sensitization, or prior to the challenge period, completely inhibited OVA-induced eosinophilic infiltration and airways responsiveness [ 23]. However, the effect of depletion of Vβ8 T cells on OVA-specific IgE antibodies varied depending on when the anti-Vβ8 mAb was given. In mice treated with antibodies to Vβ8 prior to the sensitization period, OVA challenge significantly increased the levels of OVA-specific IgE whereas treatment with anti-Vβ8 after sensitization but prior to the challenge period did not result in any increase of OVA-specific IgE levels after OVA challenge compared to saline challenged mice. This difference could be due to the different degree of Vβ8 T-cell depletion achieved in the two experiments, which was 77.2 ± 1.9% and 95.8 ± 0.9% of splenic Vβ8 T cells, respectively. In addition to the decrease in eosinophil numbers seen in BAL, treatment with anti-Vβ8 antibodies also inhibited cellular inflammation in lung tissue of OVA-challenged mice. To explore this further Hofstra et al. repeated the sensitization and challenge in two strains of mice that share the H-2c MHC type but lack Vβ8 T cells. In keeping with the results in BALB/c mice, OVA-challenge did not induce eosinophilic infiltration or airways hyperresponsiveness in either of the Vβ8-deficient strains. It is interesting to note that OVA challenge upregulated OVA-specific IgE in one of the Vβ8-deficient strains, but not in the other strain [ 23]. In interpreting these results, it is important to remember that the restriction of T-cell recognition of OVA to Vβ8+ cells applies only to this MHC-type (H-2c). As discussed above, the immune response to OVA in BALB/c mice is mediated via T cells that use a limited set of TCRs, predominantly Vβ8 and less frequently Vβ2 and Vβ14 [ 26, 27]. The epitope recognized by Vβ8 T cells is the peptide OVA323–329, but the epitope recognized by the Vβ2 and Vβ14 T cells is not yet defined. Since T cells recognize an antigen-MHC complex, and the T-cell repertoire is shaped by the host MHC type, OVA will be recognized in other strains of mice by T cells using other Vβ genes. Nevertheless, these data do allow some general conclusions to be drawn. Firstly these data indicate the important role of Vβ8 T cells in IgE synthesis and are consistent with the well-known T-cell dependence of IgE isotype switching. However, the intriguing question is why T-cells recognizing different epitopes of the same molecule should differ in their functional capacity to regulate IgE production, depending on which bit of OVA they recognize. It seems improbable that all Vβ8 T cells are genetically programmed to support IgE production, so presumably it must reflect the context in which the antigen is presented. We know that human T-cell responses are differentially regulated by the B-7 homologues CD80 and CD86 [ 28]. One could imagine that OVA may be processed differently by different antigen-presenting cells (APC) and those APCs which present the epitope seen by Vβ8 T cells might deliver costimulatory signals that would favour development towards the Th2 phenotype. The epitopes seen by non-Vβ8 T cells might be presented by functionally distinct APCs which do not favour T-cell differentiation towards assistance for IgE production. Some support for this is provided by data showing that Vβ8 T cells from OVA-sensitized mice produced significantly more IL-4 but less IFN-γ than similar numbers of Vβ2 T cells, following stimulation with anti-Vβ8 or anti-Vβ2 mAbs, respectively [ 29]. Moreover, the upregulation of OVA-specific IgE in SJL/J mice despite the lack of Vβ8 T cells, as well as in BALB/c mice treated with anti-Vβ8 antibodies prior to the sensitization, suggests that although OVA-specific Vβ8 T cells seem to determine the magnitude of IgE levels, they are not absolutely essential in the induction of antigen-specific IgE in this model. Much more importantly, the abolition of airways eosinophilia and airways hyperresponsiveness, when Vβ8 T cells are depleted, indicates that these two phenomena are critically dependent on antigen-specific T cells and cannot simply be elicited by IgE-dependent mast-cell degranulation. This conclusion is also supported by another study using this model, in which passive transfer of activated Vβ8 T cells from sensitized mice to naive recipients increased tracheal responsiveness (as measured in vitro by electric field stimulation) whereas co-transfer of activated Vβ2 T cells prevented this response [ 30]. Based on our knowledge of the cells involved, it is generally agreed the effect of T cells on eosinophilia and airways hyperresponsiveness are mediated through the release of T-cell cytokines, especially IL-5. In previous studies it has been shown that treatment with antibodies to IL-5 could completely abolish allergen-induced BAL eosinophilic infiltration in mice without affecting airways hyperresponsiveness which was in fact IFN-γ-dependent [ 31]. Other studies have also confirmed that the recruitment of eosinophils to the murine airways does not automatically induce bronchial hyperresponsiveness [ 323334] and one of these studies suggested that IL-4 might be critical [ 33]. In guinea-pig models of asthma, anti-IL-5 mAb suppressed both allergen-induced eosinophilia and airways hyperresponsiveness [ 35, 36]. Similar results were obtained in a monkey model of asthma [ 37]. The relative contributions of IgE, IL-4 and IL-5 to the development of airways hyperresponsiveness and eosinophilic infiltration have been explored further using transgenic and gene knock-out technology. Airways hyperresponsiveness could not be induced in IL-5 knock-out mice after ovalbumin sensitization and challenge [ 38] while in an IL-5 transgenic mouse, enhanced eosinophil responses were seen after immunization and after antigen challenge, but with no increase in airways responsiveness [ 39]. Paradoxically, in IgE-knock out mice, antigen-induced eosinophilic infiltration into the airways lavage was observed [ 40] while in wild-type mice, treatment with antibodies to IgE completely prevented the recruitment of eosinophils into the lungs [ 41]. Thus the complexities of the relationship of IL-4, IL-5 and IgE in regulating airways eosinophilia and hyperresponsiveness still remain to be unravelled. These studies provide further encouragement to those of us that believe in the importance of T cells in the pathogenesis of asthma and support the view that we should be targeting T-cell function and the pro-asthma cytokines such as IL-5 rather than the mechanisms involved in atopic sensitization such as IL-4 and IgE. The restricted use of TCR V-region genes to recognize certain epitopes could also allow the application of unique strategies of specific immune intervention for those allergies where a restricted range of antigens are involved. One example of the potential of this approach comes from the model of myelin basic protein (MBP) -induced experimental allergic encephalomyelitis (EAE), which is considered to be a paradigm for T-cell-mediated autoimmune disease and has striking similarities in its pathology with multiple sclerosis in humans. The major T-cell response to MBP involves T cells expressing either Vβ8 or Vβ13 gene segments and it has been shown that treatment with a combination of anti-Vβ8 and anti-Vβ13 antibodies can both prevent and treat EAE [ 42]. Therapeutic strategies using antibodies reactive to TCR family specific or idiotypic determinants would have the theoretical advantage of deleting only very specific subsets of T cells, as opposed to strategies directed against CD4 or other more widely expressed surface markers. However, this approach is limited by the need to produce anti-Vß or anti-idiotypic antibodies that can react with the relevant T cells from individuals with different MHC haplotypes." @default.
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• W1995797755 title "Regulation of allergy and asthma by T-cell Vβ family subsets" @default.
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