IL‐28A (IFN‐λ2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease

Abstract

IL-28 (IFN-λ) cytokines exhibit potent antiviral and antitumor function but their full spectrum of activities remains largely unknown. Recently, IL-28 cytokine family members were found to be profoundly down-regulated in allergic asthma. We now reveal a novel role of IL-28 cytokines in inducing type 1 immunity and protection from allergic airway disease. Treatment of wild-type mice with recombinant or adenovirally expressed IL-28A ameliorated allergic airway disease, suppressed Th2 and Th17 responses and induced IFN-γ. Moreover, abrogation of endogenous IL-28 cytokine function in IL-28Rα−/− mice exacerbated allergic airway inflammation by augmenting Th2 and Th17 responses, and IgE levels. Central to IL-28A immunoregulatory activity was its capacity to modulate lung CD11c+ dendritic cell (DC) function to down-regulate OX40L, up-regulate IL-12p70 and promote Th1 differentiation. Consistently, IL-28A-mediated protection was absent in IFN-γ−/− mice or after IL-12 neutralization and could be adoptively transferred by IL-28A-treated CD11c+ cells. These data demonstrate a critical role of IL-28 cytokines in controlling T cell responses in vivo through the modulation of lung CD11c+ DC function in experimental allergic asthma.

Borrelia burgdorferi RNA Induces Type I and III Interferons via Toll-Like Receptor 7 and Contributes to Production of NF-κB-Dependent Cytokines

“…Type I and type III IFNs share a variety of biological activities that contribute to antiviral responses, including induction of major histocompatibility complex class I antigen presentation, promotion of NK cell and T cell cytotoxic effects, and transcriptional induction of a subset of interferon-stimulated genes (75,77,(83)(84)(85). Although typically associated with antiviral responses, type III IFNs are able to attenuate the T-helper 2 (Th2) response by limiting inflammation during immune challenge, leading to tolerance; in these instances, DCs were identified to be the predominant cell populations producing IFN- (86,87). Recent studies have established a role for type III IFNs in the pathogenesis of certain bacteria, including Staphylococcus aureus, Pseudomonas aeruginosa, and L. monocytogenes (88)(89)(90)(91).…”

Impaired secretion of interferons by dendritic cells from aged subjects to influenza

“…More recently, a very important role for IFN-III was reported in protection from allergic airway disease. IFN-III levels were found to be profoundly downregulated in allergic asthma which led to exacerbation of allergic airway inflammation by augmenting Th2 and Th17 responses, and IgE levels (Koltsida et al 2011). Therefore, profound decline in the production of IFN-III would not only increase the risk of elderly population to influenza and other respiratory infections but may also be responsible for development of asthma in the elderly as poorly resolve respiratory infections are often the forerunners of asthma attacks in the population.…”

Impact of host genetic polymorphisms on vaccine induced antibody response

“…62 Quantitative real-time PCR investigations have shown, that IFNL3 expression in individuals carrying the minor allele in one or both alleles was lower in PBMCs. 70 In vitro studies showed that IFNL3 suppressesTh2-cytokines [74][75][76][77] and modulates B-cell function. 62,78 Although the impact of IFN-λ on immune cells is not yet understood, these studies indicate that IFNL3 is an important regulator of the Th1/Th2 balance and modulates viral clearance/antibody response.…”