Humans harbor a substantial Natural Killer (NK) cell compartment in their secondary lymphoid organs. These NK cells are enriched for immunoregulatory CD56brightCD16- cells, which are preferentially activated by dendritic cells (DCs). Our preliminary data demonstrate that NK cell activation by DCs restricts B cell transformation by the Epstein Barr virus (EBV) in vitro, especially when the NK cells are derived from tonsils, the secondary lymphoid organ of primary EBV infection. EBV is a human tumorvirus, which establishes latent infection in more than 90% of the human adult population. It causes tumors of epithelial and B cell origin in immune competent, and at increased frequencies in immune compromised individuals. The characterization of innate immunity to EBV is of particular interest, because failure of this initial immune control might result in increased viral titers and massive T cell expansion during primary immune responses, resulting in infectious mononucleosis. In order to characterize the role of DC/NK cell interactions during EBV infections, we plan to: 1. Characterize innate NK cell activation during EBV infection. We will dissect DC/NK cell synapse formation, DC activation by EBV derived dsRNA, and tonsillar DC subsets for their activation by EBV. 2. Analyze the protective effector functions of tonsillar NK cells. We will focus on cytokine production, cytotoxicity and assistance in protective T cell polarization by NK cells after DC activation via EBV infection. 3. Investigate EBV infection in vivo. In order to translate our in vitro findings into an in vivo model of primary EBV infection, we have reconstituted human immune systems in immune compromised mice, which could mount primary protective immune responses against EBV. This model will be explored to investigate NK cell expansion and activation during primary EBV infection, the contribution of NK cells to innate immune control of EBV, and their assistance in T cell polarization of adaptive immune control of EBV. These studies will characterize the mechanisms of NK cell activation by DCs, and protective NK cell functions against B cell transformation by oncogenic EBV in vitro and in vivo. Knowledge of the establishment of protective EBV specific immune control might suggest vaccination strategies against common EBV associated tumors like nasopharyngeal carcinoma and Hodgkin's lymphoma.

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Epstein Barr virus (EBV) causes tumors of epithelial and B cell origin in the human population, like Hodgkin's lymphoma and nasopharyngeal carcinoma. This proposal plans to investigate how two cell types of the innate immune system, dendritic cells and Natural Killer cells, interact to initially control EBV and influence other immune cells to establish life-long protection from the development of EBV associated malignancies. An understanding of these initial events during the establishment of EBV specific immune control will help us explain why some individuals develop symptomatic acute infection with EBV, called infectious mononucleosis, and identify immune compartments that should be harnessed to efficiently vaccinate against EBV associated tumors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Howcroft, Thomas K
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University of Zurich
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