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| My research program is focused upon the mechanisms of activation of natural killer (NK) cells and the interactions between NK cells and dendritic cells in the settings of viral infection and allogeneic hematopoietic stem cell transplantation | ||||||
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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-γ, TNFα), 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 interactions with other important immune cell subsets, such as dendritic cells (DC). Although NK cells lack a clonally rearranged antigen receptor, these ‘innate’ lymphocytes are capable of mounting specific responses during viral infection, such as those mediated by the activating Ly49H receptor following engagement with murine cytomegalovirus-infected cells expressing the viral GPI-anchored glycoprotein, m157. 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 two mouse models of viral infection in which NK cells execute vital immune responses: murine cytomegalovirus (MCMV) and mouse-adapted influenza A virus (IAV). Both projects implement complementary in vitro and in vivo experimental systems that examine detailed structural parameters of the molecules regulating NK cell activation (e.g., the m157-Ly49H interaction), as well as the broader aspects of defining NK cell effector functions that contribute to viral control and survival in IAV-infected mice. Our experimental design includes a powerful retroviral transduction system to isolate Ly49 receptor-mediated activation in reporter cells and an innovative NK cell depletion/reconstitution protocol that exploits the growing number of mouse strains carrying targeted mutations in genes that are important for NK cell functions. |
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| Selected Publications | ||||||
| Click Here for a Complete List of Articles | ||||||
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Heusel J.W. and Ballas, Z.K. Natural killer cells: emerging concepts in immunity to infection and implications for assessment of immunodeficiency. Curr. Opin. Pediatr. 15:586-593, 2003.
Smith, H.R.C., Heusel J.W., Mehta, I.K., Beckman, D.L., Pingel, J.T., and Yokoyama, W.M. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl. Acad. Sci. USA 99:8826-31, 2002. Brown, M.G., Dokun, A.O., Heusel J.W., Smith, H.R.C., Beckman, D.L., Blattenberger, E.A., Dubblede, C.E., Stone, L.R., Scalzo, A.A., and Yokoyama, W.M. Vital involvement of a natural killer cell receptor in resistance to viral infection. Science 292:934-937, 2001. Ho, E.L., Heusel J.W., Brown, M.G., Matsumoto, K., Scalzo, A.A., and Yokoyama, W.M. Murine Nkg2d and Cd94 are clustered within the natural killer complex and are expressed independently in natural killer cells. Proc. Natl. Acad. Sci. 95:6320-6325, 1998. |
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| Department/Program Affiliations |
| Pathology |
| MSTP |
| Biosciences |
| Immunology |