Prior exposure to inhaled allergen enhances anti-viral immunity and T cell priming by dendritic cells

Abstract

Influenza and asthma are two of the major public health concerns in the world today. During the 2009 influenza pandemic asthma was found to be the commonest comorbid illness of patients admitted to hospital. Unexpectedly, it was also observed that asthmatic patients admitted to hospital with influenza infection were less likely to die or require admission to intensive care compared with non-asthmatics. Using an in vivo model of asthma and influenza infection we demonstrate that prior exposure to Blomia tropicalis extract (BTE) leads to an altered immune response to influenza infection, comprised of less severe weight loss and faster recovery following infection. This protection was associated with significant increases in T cell numbers in the lungs of BTE sensitised and infected mice, as well as increased IFN-γ production from these cells. In addition, elevated numbers of CD11b+ dendritic cells (DCs) were found in the lung draining lymph nodes following infection of BTE sensitised mice compared to infected PBS treated mice. These CD11b+ DCs appeared to be better at priming CD8 specific T cells both in vivo and ex vivo, a function not normally attributed to CD11b+ DCs. We propose that this alteration in cross-presentation and more efficient T cell priming seen in BTE sensitised mice, led to the earlier increase in T cells in the lungs and subsequently faster clearance of the virus and reduced influenza induced pathology. We believe this data provides a novel mechanism that explains why asthmatic patients may present with less severe disease when infected with influenza.

Influenza in Asthmatics: For Better or for Worse?

“…Using a clinically relevant mouse model of severe asthma with fungal sensitization, we showed that acute allergic inflammation induced by allergen provocation protected mice from pH1N1-induced influenza, while chronic remodeling that resulted from fungal challenge made mice susceptible to influenza morbidity and host pathology ( 139 ) highlighting the impact of the temporal association between allergen provocation and viral infection in disease outcome during asthma and influenza. The discovery that mice with heightened allergic responses in the lungs had less severe influenza were later confirmed by other groups ( 158 , 160 , 162 ) all using different allergens suggesting that this outcome is common to allergic asthma. Ovalbumin-induced allergic airways disease was resistant to lethal pH1N1 infections ( 158 ) through mechanisms that involved the TGF-β pathway ( 163 ) (Figure 5 ).…”

“…Our characterization of antiviral responses in hosts with acute and chronic asthma showed that viral clearance was enhanced in mice with acute allergic asthma which also had elevated influenza-specific CD8 + T cells ( 139 ), which we subsequently determined to be due to putative antigen-presenting functions in eosinophils that enhanced cellular immunity ( 167 ) (Figure 5 ). Others have shown that CD11b + DCs are better at CD8 + T cell activation in context of asthma and influenza co-morbidity ( 160 ) (Figure 5 ). Neutrophils provide additional support for cellular immune responses during influenza by guiding the migration of CD8 + T cells into the lungs ( 168 ).…”

Coincident airway exposure to low-potency allergen and cytomegalovirus sensitizes for allergic airway disease by viral activation of migratory dendritic cells

“…In a sense, our model is a co-morbidity model in that it links CMV infection to AAD. Notably, while we have shown that viral activation of CD11b + cDCs in airway mucosa promotes Th2-driven AAD, a mirror image was recently presented by linking AAD/asthma to influenza virus infection [79]. In that work, prior airway exposure to an inhaled potent allergen activated the CD11b + cDCs in the airway mucosa and their migration into the draining LNs, which unexpectedly resulted in a more efficient priming of protective antiviral CD8 + T cells, a function usually attributed in influenza virus infection to the antigen cross-presenting CD103 + cDCs [80].…”

Impact of Therapeutics on Unified Immunity During Allergic Asthma and Respiratory Infections

“…Experimental models of allergic asthma and influenza have effectively recapitulated that allergic immunity protects the host from severe influenza ( 62 – 68 ). This protective effect has been attributed to enhanced NK cell activation ( 63 ), CD8 + T cell support provided by eosinophils ( 62 , 65 ), transforming growth factor (TGF)-β1-induced reduction of inflammation ( 64 ), CD11b + DCs ( 67 ), and most recently, eosinophil-mediated enhancement of epithelial barrier responses ( 68 ). The timing of IAV infection in relation to asthma induction and the state of the allergic airways during infection are crucial for disease outcome.…”