Regulation of the adaptive immune response to inhaled allergens.

Abstract

The airway is exposed to a continuous stream of environmental antigens and occasional opportunistic pathogens. This necessitates the development of a mucosal immune system that fulfils a protective immunosurveillance role yet fails to respond to innocuous antigens. Antigen-presenting cells (APCs) resident in the airway are thought to play a pivotal role in such decisions. The most efficient APCs are dendritic cells (DCs), which, in the lung, are found in intimate contact with the airway epithelium and are ideally located to sample antigens entering the airway [1]. Such immature DCs are highly endocytic and thus well adapted for the capture of antigen, but are poor at antigen presentation. Exposure of such immature DCs to lipopolysaccharide (LPS), bacterial DNA and other pathogen-associated molecular patterns (PAMPs) markedly increases their ability to present antigen [2] and prompts their migration away from the lung to the draining lymph nodes [3]. Toll-like receptors (TLRs) on DCs have been shown to play a critical role in the recognition of antigens expressed by pathogens such as LPS (TLR4) and PAMPs (TLR2 and TLR9), each alerting the immune system to the presence of infectious agents [4-6]. In contrast to the response to pathogens, the response to inhaled soluble antigens displays evidence of severe immune regulation [7]. Such immune unresponsiveness to soluble antigens is a characteristic feature of both the intestinal and lung mucosa. However, marked differences exist in the type and number of T cells present at these two mucosal sites. Most notably, in the intestine large numbers of CD8+ intraepithelial T cells expressing the αEβ7 integrin are present, while in the lung very few intraepithelial T cells are found. In addition, Th1 responses predominate in the intestine, whilst Th2 responses occur more frequently in the lung. Consequently, the onset of unresponsivness to inhaled or ingested soluble antigens may reflect events either idiosyncratic to the mucosal environment or alternatively arise from disparate responses to innocuous vs. pathogen antigens. There is increasing evidence that regulation of the T cell response to inhaled antigens exists at several levels. The inflammatory response in the lung to soluble antigens is a self-limiting process in which mediators generated during the response (such as IL-10, TGF-β and prostanoids) exert pronounced immunomodulatory effects on mucosal T cells. Moreover, using a model of Th1- and Th2-mediated pulmonary inflammation, lung interstitial macrophages were demonstrated to prevent clonal expansion of T cells at the mucosal site by a contact-dependent mechanism [8]. In addition, PGI2 generated during inflammatory responses played a critical role in limiting the progression of the type 2, but not type 1 response [9]. Continued inhalation of soluble antigen has further systemic effects that serve to modulate the immune response. In this context, exposure of rodents to aerosolized ovalbumin (OVA) resulted in the initial production of IgE [10], however, continued exposure of either mice or rats to aerosolized antigen inevitably led to a marked reduction in the serum IgE levels. A potential role for class I restricted CD8+γδ+T cells in the onset of such aerosol-induced unresponsiveness was proposed [11, 12]. Initially this was explained by the deviation of the CD4+ response which switched from a Th2 profile to that of a Th1 [13]. Further insight into this effect was provided by the demonstration that aerosol exposure had a marked effect on the immune response of animals following subsequent immunization with OVA. Interestingly, mice exposed to aerosolized OVA have been shown to display reduced IgE responses on subsequent immunization with OVA using an alum adjuvant [14]. Associated with this reduction was the marked attenuation of Th2 response, however, no role for IFN-γ, CD8+ or γδ+ T cells could be found in mediating this effect. In the current issue of Clinical & Experimental Allergy, Swirski et al. demonstrate that OVA inhalation is associated with a marked reduction in the T cell response on subsequent immunization with OVA using an alum adjuvant [15]. This is evident by a reduction in proliferative responses and the production of both Th1 and Th2 cytokines in response to OVA. Associated with such immunomodulation was a reduction in the levels of pulmonary eosinophila induced following OVA inhalation and the airway hyper-reactivity. Interestingly, in both studies the production of IgG1 is not affected by OVA inhalation, implying that there is a level of discordance between the B cell response and the underlying T cell response. If unresponsiveness was a consequence of the soluble antigen being non-pathogenic, it might be expected that such tolerance could be averted in the presence of an immune response to a pathogen. Interestingly, primary responses to Nippostrongylus larvae or Asperigillus fumagatus extract prevented establishment of IgE tolerance to aerosolized OVA [16]. In contrast, concurrent Th1 responses to influenza virus or Mycobacterium bovis bacillus Calmette-Guerin had no effect. However, once established, aerosol tolerance to OVA could not be completely broken by A. fumagatus extract, implying that aerosol-induced IgE tolerance may not be appropriately established in individuals undergoing concurrent Th2-mediated responses to antigens or pathogens [16]. These findings suggest that tolerance induction is not idiosyncratic to the mucosal environment, but arises as a consequence of differences in the way the immune system responds to soluble vs. pathogenic antigens. The mechanism of this aerosol-induced IgE unresponsiveness and associated T cell tolerance is unclear. A role for IL-10 has been demonstrated in the induction of tolerance to inhaled antigen since administration of a neutralizing antibody to IL-10 prevented the onset of tolerance to antigen [17]. DCs prepared from the airway produce IL-10, promote T regulatory responses and favour tolerance induction [18]. Pulmonary DCs found in the bronchial lymph nodes following OVA inhalation produce IL-10 which induce a state of OVA-specific unresponsiveness following adoptive transfer to normal mice [18]. However, IgE unresponsiveness has been shown to occur in mice in which the IL-10 gene has been deleted [15]. These data suggest that IL-10 may play an important role in the induction of T cell tolerance to inhaled antigens but is not in itself responsible for IgE unresponsiveness. Delivery of a peptide or protein antigen intranasally leads inextricably to a state of systemic tolerance [19]. Entry into this state involves the initial transient proliferative phase and this is typically associated with a primary antibody response but no isotype switching. The state of tolerance is characterized by a marked decrease in the production of both Th1 and Th2 cytokines and reduced proliferative responses [20]. This tolerance is directed normally to all T cell epitopes in an antigen, a phenomena known as linked suppression. It has recently been demonstrated that a small proportion of peripheral T cells in normal animals express CD25 [21]. These T cells are known to regulate T cell responses and can prevent both the development of autoimmune conditions [22] and the onset of colitis [23]. Regulatory T cells mediate suppression by several different routes which include their production of IL-10 and TGF-β and by contact-dependent mechanisms [21]. A role for deletion and anergy induction as a driving force in tolerance induction has been suggested. However, more recently a role for CD4+ regulatory T cells has been proposed in driving active suppression. CD4+CD25+ T regulatory cells have been implicated in mediating tolerance elicited by intranasal administration of peptide antigens [24]. In summary, there is cumulative evidence using murine models of asthma that lung mucosal Th2 responses are self-limiting. This raises several implications pertaining to how the progression of allergic inflammatory responses in the lung is normally prevented in humans. It is interesting to speculate that chronic airway inflammatory diseases such as asthma arise as a consequence of a defect in such regulatory events.