Down-regulation of natural killer cell activation in response to influenza virus in older adults

Immune senescence contributes to influenza-associated high mortality and morbidity and reduced vaccine efficacy in elderly people. Type I T cell (Th1)-mediated immunity plays a significant role in immune responses to influenza infection and vaccination. Natural killer (NK) cells secrete significant amount of IFN-gamma, a hallmark Th1 cytokine, in response to influenza infection. How aging influences human NK cell IFN-gamma production in response to influenza virus has not been well documented. In this study we employed human peripheral blood mononuclear cells (PBMC) and performed intracellular cytokine staining and flow cytometry primarily to investigate how aging influences NK cell activation with respect to IFN-gamma production in response to influenza virus. We have found that NK cell IFN-gamma production, mediated by both soluble factors and cell-cell contact factors is down-regulated in elderly subjects compared to young subjects in response to influenza virus. As for soluble factors, IFN-alpha and IFN-gamma are proven to be important in inducing NK cell to produce IFN-gamma. The frequencies of IFN-alpha-producing plasmacytoid dendritic cells (pDC) and IFN-gamma-producing T cells in PBMC are lower in the elderly subjects than in the young subjects. Further more, pDC from the young subjects produce more IFN-alpha on a per-cell basis and mediate NK cells to produce more IFN-gamma than pDC from the elderly subjects. As for cell-cell contact factors, the expressions of NKp44 and NKp46, two natural cytotoxicity receptors on NK cell surface specifically recognizing influenza hemagglutinin (HA) expressed on antigen presenting cells, are up-regulated upon influenza infection of PBMC, but display higher expression levels in older subjects than young subjects. Our data have demonstrated that agingrelated numerical and/or functional impairment in pDC and T cells results in lower production of IFN-alpha and IFN-gamma, and consequently contributes to the down-regulation of IFN-gamma production in NK cells in response to influenza virus in older adults. How aging affects NK cell IFN-gamma production through influencing cell-cell contact regulation between NK cells and antigen presenting cells remains to be elusive. It's our strong belief that our study and the related findings will help enrich our knowledge about how aging affects innate as well as adaptive immune system in response to influenza virus, and help build the fundamentals for developing more effective prophylactic and therapeutic approaches to fulfill the long-term goal of reducing influenza morbidity and mortality and improving the quality of life for the elderly.