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Research Program description Natural killer (NK) cells are a heterogeneous population of lymphocytes that performs diverse biological functions, including defense against a wide variety of infectious microbes. NK cell responses include direct cytotoxicity toward infected or antibody-coated ‘target’ cells and the secretion of multiple cytokines (e.g., IFN-g, TNF-a), chemokines (e.g., CCL3-5) and growth factors (e.g. IL-3, GM-CSF). Through these effector functions NK cells are able to control the microbial load during the earliest phase of infection, and also coordinate the subsequent adaptive immune response through recruitment and activation of other important immune cell subsets, such as dendritic cells (DC). Although NK cells are not activated by antigen-specific receptors per se, NK cells are capable of mounting specific responses during viral infection. The long-term goal of our research program is to define the molecular parameters that contribute toward NK cell activation as it applies to integrated immune responses to infection, transplantation and cancer. Our laboratory utilizes a robust in vitro reporter system for cellular activation mediated by natural killer cell surface receptors. This system was instrumental in discovering a virally encoded ligand for the murine NK cell activating receptor, Ly-49H: the murine cytomegalovirus (MCMV) m157 gene product. Currently, we are dissecting the associated molecular parameters that contribute to Ly-49H-mediated activation, both in vitro and in vivo. Additionally, we have adapted this reporter system to examine human NK cell activating receptors in the killer immunoglobulin-like receptor (KIR) family in response to human herpesvirus infection (CMV, HSV, and EBV). Defining these interactions will provide important insight into which subsets of NK cells are responding to particular infections in various microenvironments, what other cells are communicating with these NK cell subsets, and which NK cell effector functions are activated by these interactions. Selected Publications Heusel JW and Ballas ZK: Natural killer cells: emerging concepts in immunity to infection and implications for assessment of immunodeficiency. Curr Opin Pediatr. 2003 Dec;15(6):586-93. Smith HRC*, Heusel JW*, Mehta IK, Beckman DL, Pingel JT, and Yokoyama WM. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc Natl Acad Sci USA 2002 June 25;99 (13):8826-31. Brown MG*, Dokun AO*, Heusel JW, Smith HRC, Beckman DL, Blattenberger EA, Dubblede CE, Stone LR, Scalzo AA, Yokoyama, WM: Vital involvement of a natural killer cell receptor in resistance to viral infection. Science 2001; 292: 934-937. Smith HRC, Chuang HH, Wang LL, Salcedo M, Heusel JW, and Yokoyama WM: Nonstochastic coexpression of activation receptors on murine natural killer cells. J Exp Med 2000; 191: 1341-1354. Ho EL*, Heusel JW*, Brown MG, Matsumoto K, Scalzo AA, Yokoyama WM: Murine Nkg2d and Cd94 are clustered within the natural killer complex and are expressed independently in natural killer cells. Proc Natl Acad Sci USA 1998; 95: 6320-6325. |
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