Accelerated Antigen Sampling and Transport by Airway Mucosal Dendritic Cells following Inhalation of a Bacterial Stimulus

Abstract

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.

Enemy at the gates: dendritic cells and immunity to mucosal pathogens

“…The sequential activation and maturation process within DC occurs en route from the mucosa to the draining lymph nodes, resulting in CCR7-directed transport to peripheral lymphatic endothelial cells as well as lymph node stroma cells expressing CCL19 and CCL21 [83,84]. Submucosal DC are found to upregulate co-stimulatory markers and assume dendriform morphology while trafficking to the draining lymph nodes following respiratory challenge with heat-killed Moraxella catarrhalis [26]. Additionally, T cell stimulatory ability is found in peribronchial lymph node populations 24 h following bacterial challenge, but is absent 2 h post-infection [26].…”

“…It is likely that these cells repre- sent a developmental continuum, with recently emigrated monocyte-derived DC of the LP undergoing further differentiation while traveling into the epithelium, as seen through slight increases in MHC-II expression, size, and dendrite expression, along with a minor decrease in endocytic activity [26]. Steady-state pulmonary DC replacement rates are differentiated by both anatomic location and DC phenotype, with upper airway DC expressing moderate levels of CD11c and undergoing rapid turnover, with greater than 80% DC exchange in 18-36 h. In contrast, DC populations of the lung parenchyma express high levels of CD11c and have reduced rates of replacement of roughly ~12% exchange in 9 days [27,28].…”

“…Confocal microscopic analysis of rat trachea revealed that under homeostatic conditions roughly 20% of resident DC interdigitate within the resting epithelium, with the remaining 80% dwelling within the subepithelial connective tissues [26]. It is likely that these cells repre- sent a developmental continuum, with recently emigrated monocyte-derived DC of the LP undergoing further differentiation while traveling into the epithelium, as seen through slight increases in MHC-II expression, size, and dendrite expression, along with a minor decrease in endocytic activity [26].…”

“…Submucosal DC are found to upregulate co-stimulatory markers and assume dendriform morphology while trafficking to the draining lymph nodes following respiratory challenge with heat-killed Moraxella catarrhalis [26]. Additionally, T cell stimulatory ability is found in peribronchial lymph node populations 24 h following bacterial challenge, but is absent 2 h post-infection [26]. This compartmentalization of functions protects mucosal tissues, particularly those seen in the airway, from T-cell-mediated damage that could ensue from continuously responding to ubiquitous nonpathogenic antigens present in ambient air.…”

Interactions between epithelial cells and dendritic cells in airway immune responses: lessons from allergic airway disease

“…Moreover, in mice, an epithelial CD103 (alphaE)-beta7 integrin-positive DC population expressing high levels of the LC-marker Langerin and the tight junction proteins Claudin-1, Claudin-7, and ZO-2 was described (56). And finally, using a three dimensional reconstruction of immunofluorescence staining of the airway mucosa of rats, 1-5% of all intra-epithelial DCs were shown to project cellular extensions between epithelial cells to the apical surface (57). These in vitro and ex vivo data imply a strong physical connection between epithelial cell and DC; tight junctions are formed to maintain the integrity of the epithelial barrier, while DCs are allowed to sample antigen at the mucosal surface by extending dendrites to the apical lumen.…”