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A hallmark of atopic asthma is development of chronic airways hyper-responsiveness (AHR) that persists in the face of ongoing exposure to perennial aeroallergens. We investigated underlying mechanisms in sensitized rats focusing on a strain expressing the high-allergen-responder phenotype characteristic of human atopic asthmatics, and find that their high susceptibility to aeroallergen-induced persistent AHR is associated with deficiencies in the immunoregulatory and mucosal trafficking properties of inducible T-regulatory cells (iTregs). Counterintuitively, AHR susceptibility was inversely related to aeroallergen exposure level, high exposures conferring protection. We demonstrate that underlying this AHR-susceptible phenotype is reduced capacity of airway mucosal dendritic cells (AMDCs) for allergen sampling in vivo; this defect is microenvironmentally acquired, as allergen uptake by these cells in vitro is normal. Moreover, intranasal transfer of in vitro aeroallergen-loaded AMDC from naïve animals into AHR-susceptible animals during prolonged aerosol challenge markedly boosts subsequent accumulation of iTregs in the airway mucosa and rapidly resolves their chronic AHR, suggesting that compromised antigen surveillance by AMDC resulting in defective functional programming of iTreg may be causally related to AHR susceptibility.

Asthma is a chronic disease of the airways, most commonly driven by immuno-inflammatory responses to ubiquitous airborne antigens. Epidemiological studies have shown that disease is initiated early in life when the immune and respiratory systems are functionally immature and less able to maintain homeostasis in the face of continuous antigen challenge. Here, we examine the cellular and molecular mechanisms that underlie initial aeroallergen sensitization and the ensuing regulation of secondary responses to inhaled allergens in the airway mucosa. In particular, we focus on how T-regulatory (Treg) cells influence early asthma initiation and the potential of Treg cells as therapeutic targets for drug development in asthma., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The respiratory tract has an approximate surface area of 70 m2 in adult humans, which is in virtually direct contact with the outside environment. It contains a uniquely rich vascular bed containing a large pool of marginated T cells, and harbours a layer of single-cell-thick epithelial tissue through which re-oxygenation of blood must occur uninterrupted for survival. It is therefore not surprising that the respiratory tract is never more than a short step away from disaster. We have only a partial understanding of how immunological homeostasis is maintained in these tissues, but it is becoming clear that the immune system has evolved a range of specific mechanisms to deal with the unique problems encountered in this specialized microenvironment.

Airway mucosal dendritic cells (AMDC) and other airway APCs continuously sample inhaled Ags and regulate the nature of any resulting T cell-mediated immune response. Although immunity develops to harmful pathogens, tolerance arises to nonpathogenic Ags in healthy individuals. This homeostasis is thought to be disrupted in allergic respiratory disorders such as allergic asthma, such that a potentially damaging Th2-biased, CD4(+) T cell-mediated inflammatory response develops against intrinsically nonpathogenic allergens. Using a mouse model of experimental allergic airways disease (EAAD), we have investigated the functional changes occurring in AMDC and other airway APC populations during disease onset. Onset of EAAD was characterized by early and transient activation of airway CD4(+) T cells coinciding with up-regulation of CD40 expression exclusively on CD11b(-) AMDC. Concurrent enhanced allergen uptake and processing occurred within all airway APC populations, including B cells, macrophages, and both CD11b(+) and CD11b(-) AMDC subsets. Immune serum transfer into naive animals recapitulated the enhanced allergen uptake observed in airway APC populations and mediated activation of naive allergen-specific, airway CD4(+) T cells following inhaled allergen challenge. These data suggest that the onset of EAAD is initiated by enhanced allergen capture and processing by a number of airway APC populations and that allergen-specific Igs play a role in the conversion of normally quiescent AMDC subsets into those capable of inducing airway CD4(+) T cell activation.

An important feature of atopic asthma is the T cell-driven late phase reaction involving transient bronchoconstriction followed by development of airways hyperresponsiveness (AHR). Using a unique rat asthma model we recently showed that the onset and duration of the aeroallergen-induced airway mucosal T cell activation response in sensitized rats is determined by the kinetics of functional maturation of resident airway mucosal dendritic cells (AMDCs) mediated by cognate interactions with CD4+ T helper memory cells. The study below extends these investigations to chronic aeroallergen exposure. We demonstrate that prevention of ensuing cycles of T cell activation and resultant AHR during chronic exposure of sensitized rats to allergen aerosols is mediated by CD4+CD25+Foxp3+LAG3+ CTLA+CD45RC+ T cells which appear in the airway mucosa and regional lymph nodes within 24 h of initiation of exposure, and inhibit subsequent Th-mediated upregulation of AMDC functions. These cells exhibit potent regulatory T (T reg) cell activity in both in vivo and ex vivo assay systems. The maintenance of protective T reg activity is absolutely dependent on continuing allergen stimulation, as interruption of exposure leads to waning of T reg activity and reemergence of sensitivity to aeroallergen exposure manifesting as AMDC/T cell upregulation and resurgence of T helper 2 cytokine expression, airways eosinophilia, and AHR.

An increase in the tempo of local dendritic cell (DC)-mediated immune surveillance is a recognized feature of the response to acute inflammation at airway mucosal surfaces, and transient up-regulation of the APC functions of these DC preceding their emigration to regional lymph nodes has recently been identified as an important trigger for T cell-mediated airway tissue damage in diseases such as asthma. In this study, using a rat model, we demonstrate that the kinetics of the airway mucosal DC (AMDC) response to challenge with heat-killed bacteria is considerably more rapid and as a consequence more effectively compartmentalized than that in recall responses to soluble Ag. Notably, Ag-bearing AMDC expressing full APC activity reach regional lymph nodes within 30 min of cessation of microbial exposure, and in contrast to recall responses to nonpathogenic Ags, there is no evidence of local expression of APC activity within the airway mucosa preceding DC emigration. We additionally demonstrate that, analogous to that reported in the gut, a subset of airway intraepithelial DC extend their processes into the airway lumen. This function is constitutively expressed within the AMDC population, providing a mechanism for continuous immune surveillance of the airway luminal surface in the absence of "danger" signals.

APCs, including dendritic cells (DC), are central to Ag surveillance in the respiratory tract (RT). Research in this area is dominated by mouse studies on purportedly representative RT-APC populations derived from whole-lung digests, comprising mainly parenchymal tissue. Our recent rat studies identified major functional differences between DC populations from airway mucosal vs parenchymal tissue, thus seriously questioning the validity of this approach. We addressed this issue for the first time in the mouse by separately characterizing RT-APC populations from these two different RT compartments. CD11c(high) myeloid DC (mDC) and B cells were common to both locations, whereas a short-lived CD11c(neg) mDC was unique to airway mucosa and long-lived CD11c(high) macrophage and rapid-turnover multipotential precursor populations were predominantly confined to the lung parenchyma. Airway mucosal mDC were more endocytic and presented peptide to naive CD4+ T cells more efficiently than their lung counterparts. However, mDC from neither site could present whole protein without further maturation in vitro, or following trafficking to lymph nodes in vivo, indicating a novel mechanism whereby RT-DC function is regulated at the level of protein processing but not peptide loading for naive T cell activation.