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

Abstract

Increased susceptibility to respiratory infections such as influenza is the hallmark of advancing age. The mechanisms underlying the impaired immune response to influenza are not well understood. In the present study, we have investigated the effect of advancing age on dendritic cell (DC) function because they are critical in generating robust antiviral responses. Our results indicate that monocyte derived DCs from the aged are impaired in their capacity to secrete interferon (IFN)-I in response to influenza virus. Additionally, we observed a severe reduction in the production of IFN-III, which plays an important role in defense against viral infections at respiratory mucosal surfaces. This reduction in IFN-I and IFN-III were a result of age-associated modifications in the chromatin structure. Investigations using chromatin immunoprecipitation with H3K4me3 and H3K9me3 antibodies revealed that there is increased association of IFN-I and IFN-III promoters with the repressor histone, H3K9me3 in non-stimulated aged DCs compared to young DCs. This was accompanied by decreased association of these promoters with activator histone, H3K4me3 in aged DCs after activation with influenza. In contrast to interferons, the association of TNF-alpha promoter with both these histones was comparable between aged and young subjects. Investigations at 48 h suggested that these changes are not stable and change with time. In summary, our study demonstrates that myeloid DCs from aged subjects are impaired in their capacity to produce IFNs in response to influenza virus and that age-associated altered histone expression patterns are responsible for the decrease in IFN production.

Dendritic cells from aged subjects contribute to chronic airway inflammation by activating bronchial epithelial cells under steady state

“…12 These include their capacity to phagocytose antigens, 13 migration to lymph nodes, 13 response to pathogens, 14,15 and impaired secretion of certain key cytokines such as IFN-α and IFN-l. 14–16 Furthermore, DCs from the elderly display increased basal level of activation as evidenced by increased activation of nuclear factor κB, 17 which has a major role in the secretion of pro-inflammatory mediators by DCs. Increased basal level nuclear factor κB activation in aged DCs may result in an enhanced secretion of various molecules under steady state, in the absence of infection.…”

Immune System Dysfunction in the Elderly

“…Therefore the production of TNF-α is a determining factor in the dC-mediated Cd8+ T cell response against influenza (liu et al 2012). In addition, a comparison of the antigenpresenting capacity of aged plasmacytoid dendritic cell (PDC) with young PDC revealed that PDC from aged subjects displays reduced capacity to induce proliferation and IFN-γ secretion in Cd4+ and CD8+ T cells as compared with PDC from young subjects (Sridharan et al 2011, Prakash et al 2013). …”

Nutrition, diet and immunosenescence

“…Impaired IFN-I and -III production by pDCs may be linked to an alteration in IRF-7 phosphorylation, which is impaired in DCs of aged subjects but increased in young subjects (Sridharan et al, 2011). Recent findings reveal that the age-associated reduction in the ability of monocyte derived DCs to produce IFN-I and III in response to influenza virus is linked to alterations in chromatin structure (Prakash et al, 2012). Surface expression of CD54 and MHC II that improve contact between APCs and T cells is comparable between young and elderly subjects with increases observed upon exposure to influenza vaccine and in the production of IL-12 and TNF-α (SaurweinTeissl et al, 1998).…”