Date of Award

Spring 2007

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

Program/Concentration

Biomedical Sciences

Committee Director

Yuping Deng

Committee Member

Stefan Gravenstein

Committee Member

Ann Campbell

Committee Member

Mark Birkenbach

Abstract

Immune senescence contributes to influenza-associated high mortality and morbidity and reduced vaccine efficacy in elderly people. Type I T cell (Thl)-mediated immunity plays a significant role in Immune responses to influenza infection and vaccination. Natural killer (NK) cells secrete significant amount of IFN-7 , a hallmark Thl cytokine, in response to influenza infection. How aging influences human NK cell IFN-7 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- 7 production in response to influenza virus. We have found that NK cell IFN- 7 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-o: and IFN- 7 are proven to be important in inducing NK cell to produce IFN-7 . The frequencies of IFN-a-producing plasmacytoid dendritic cells (pDC) and IFN-7 -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-o: on a per-cell basis and mediate NK cells to produce more

IFN-y 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-o; and IFN-y, and consequently contributes to the down-regulation of IFN-y production in NK cells in response to influenza virus in older adults. How aging affects NK cell IFN-y 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.

DOI

10.25777/kx5s-hk41

ISBN

9780549083283

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