NK cell Immunity to Influenza

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Influenza A virus is a highly successful human pathogen which naturally kills millions of people and has both potential and advantage as a biological weapon. Natural killer (NK) cells are lymphocytes of innate immunity that play a critical role in early defense against viral infections and in the initiation of the adaptive-immune response. Recent advances in knowledge of the diverse receptor phenotypes of NK cells within the individual person and of functional NK-cell interactions with dendritic cells (DC), suggest that the extensive diversity of killer cell immunoglobulin-like receptor (KIR) genes in (and between) human populations is the result of selection by viruses for NK-cell and T-cell responses that reduce the severity and time of infection. Here we propose three specific aims to study the role of NK-cells and NKcell receptors (NKR) in the human response to influenza A, with the overall goal of defining genetic and other factors that provide for superior response. Under Aim 1 the in vitro NK-cell response to influenza A will be studied using peripheral blood NK cells obtained from donors whose NK-cell immunogenetics is well defined. Both cytolysis and cytokine production will be assessed using flow cytometry, Elispot and cell-killing assays. The contributions of activating and inhibitory receptors to NK cell interaction with autologous influenza-infected DC will be defined. Aim 2 focuses on the expression of KIR and other NKR by subpopulations of memory and/or activated T cells, a general phenomenon but one which varies greatly within the human population. The expression of NKR by influenza-specific CD8 ¿ T cells from different donors will be characterised. The types and combination of NKR will be defined and analyzed for selective bias. The effects that these receptors have on the anti-viral functions of the T cells will be determined. The analysis proposed under Aim 3 will use the methods and knowledge obtained under Aim 1 to characterise the NK-cell response in subjects infected with influenza A or vaccinated against influenza A. Comparisons of the response will assess the diversity of the response, its correlation with NK-cell immunogenetics and with age. New knowledge of the nature and diversity of the human NK-cell response to influenza and of the role of NKR expression on CD8 ¿ T cells will be obtained. These results could lead to new strategies for terminating influenza infections through the manipulation or stimulation of human NK-cells and/or NKR-expressin 9 T cells.