Restricted Aeroallergen Access to Airway Mucosal Dendritic Cells In Vivo Limits Allergen-Specific CD4+ T Cell Proliferation during the Induction of Inhalation Tolerance

Abstract

Chronic innocuous aeroallergen exposure attenuates CD4+ T cell-mediated airways hyperresponsiveness in mice; however, the mechanism(s) remain unclear. We examined the role of airway mucosal dendritic cell (AMDC) subsets in this process using a multi-OVA aerosol-induced tolerance model in sensitized BALB/c mice. Aeroallergen capture by both CD11blo and CD11bhi AMDC and the delivery of OVA to airway draining lymph nodes by CD8α− migratory dendritic cells (DC) were decreased in vivo (but not in vitro) when compared with sensitized but nontolerant mice. This was functionally significant, because in vivo proliferation of OVA-specific CD4+ T cells was suppressed in airway draining lymph nodes of tolerized mice and could be restored by intranasal transfer of OVA-pulsed and activated exogenous DC, indicating a deficiency in Ag presentation by endogenous DC arriving from the airway mucosa. Bone marrow-derived DC Ag-presenting function was suppressed in multi-OVA tolerized mice, and allergen availability to airway APC populations was limited after multi-OVA exposure, as indicated by reduced OVA and dextran uptake by airway interstitial macrophages, with diffusion rather than localization of OVA across the airway mucosal surface. These data indicate that inhalation tolerance limits aeroallergen capture by AMDC subsets through a mechanism of bone marrow suppression of DC precursor function coupled with reduced Ag availability in vivo at the airway mucosa, resulting in limited Ag delivery to lymph nodes and hypoproliferation of allergen-specific CD4+ T cells.

Size-Dependent Uptake of Particles by Pulmonary Antigen-Presenting Cell Populations and Trafficking to Regional Lymph Nodes

“…Finally, although the trafficking of particle-bearing DCs from the LP to conducting airways may account for particles seen in the conducting airways (38), we and others have shown that DCs may efficiently extend transepithelial dendrites into the airway lumen for direct antigen and possibly particle sampling (35,36,39,40).…”

“…We adopted a widely used model involving intranasal instillation to allow for the straightforward administration of particles to the airways and LP (20,30,31,35,36), and we showed a homogenous distribution of particles in the lung by flow cytometry and confocal microscopy. Nevertheless, to interpret the data in the context of the particle application method used in this study remains essential (please refer to the online data supplement).…”

Burn Injury Leads to Increased Long-Term Susceptibility to Respiratory Infection in both Mouse Models and Population Studies

“…Airway draining lymph nodes (ADLN) were prepared as single cell suspensions as described previously [48]. In brief, ADLN (upper paratracheal and parathymic) were harvested from individual mice, chopped with a scalpel, and digested with type IV collagenase (1.5mg/ml; Worthington) and type I DNase (0.1 mg/ml; Sigma-Aldrich) for 20 min at 37°C.…”

“…In brief, ADLN (upper paratracheal and parathymic) were harvested from individual mice, chopped with a scalpel, and digested with type IV collagenase (1.5mg/ml; Worthington) and type I DNase (0.1 mg/ml; Sigma-Aldrich) for 20 min at 37°C. All digestions and washes were performed in 5%FCS/glucose sodium potassium (GKN) buffer (11 mM D-glucose, 5.5 mM KCl, 137 mM NaCl, 25 mM Na2HPO4, 5.5 mM NaH2PO4.2 H2O) with debris and RBCs removed as described previously [48]. …”

Regulatory tone and mucosal immunity in asthma

“…These studies established that, in the lung, increasing regulatory tone could result in prevention of allergic sensitization in response to an exposure regimen that is well documented to cause severe lung inflammation in naïve mice. In follow up studies, several groups have demonstrated that increasing regulatory tone in naïve mice by peptide or protein immunization, or even direct injection of tolerogenic DCs or Tregs, significantly suppress subsequent allergic inflammatory responses in the lung (90-96). Therefore, there is strong evidence that robust regulatory tone can prevent allergic sensitization.…”