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.
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. ? ? ?
|Fonteneau, Jean Francois; Brilot, Fabienne; Münz, Christian et al. (2016) The Tumor Antigen NY-ESO-1 Mediates Direct Recognition of Melanoma Cells by CD4+ T Cells after Intercellular Antigen Transfer. J Immunol 196:64-71|
|Jung, Jae; Münz, Christian (2015) Immune control of oncogenic ?-herpesviruses. Curr Opin Virol 14:79-86|
|Jandus, Camilla; Boligan, Kayluz Frias; Chijioke, Obinna et al. (2014) Interactions between Siglec-7/9 receptors and ligands influence NK cell-dependent tumor immunosurveillance. J Clin Invest 124:1810-20|
|Azzi, Tarik; Lünemann, Anna; Murer, Anita et al. (2014) Role for early-differentiated natural killer cells in infectious mononucleosis. Blood 124:2533-43|
|Salguero, Gustavo; Daenthanasanmak, Anusara; Münz, Christian et al. (2014) Dendritic cell-mediated immune humanization of mice: implications for allogeneic and xenogeneic stem cell transplantation. J Immunol 192:4636-47|
|Jungraithmayr, Wolfgang; Codarri, Laura; Bouchaud, Gregory et al. (2013) Cytokine complex-expanded natural killer cells improve allogeneic lung transplant function via depletion of donor dendritic cells. Am J Respir Crit Care Med 187:1349-59|
|Romao, Susana; Gannage, Monique; Münz, Christian (2013) Checking the garbage bin for problems in the house, or how autophagy assists in antigen presentation to the immune system. Semin Cancer Biol 23:391-6|
|Leung, Carol; Chijioke, Obinna; Gujer, Cornelia et al. (2013) Infectious diseases in humanized mice. Eur J Immunol 43:2246-54|
|Meixlsperger, Sonja; Leung, Carol S; Rämer, Patrick C et al. (2013) CD141+ dendritic cells produce prominent amounts of IFN-? after dsRNA recognition and can be targeted via DEC-205 in humanized mice. Blood 121:5034-44|
|Chijioke, Obinna; Azzi, Tarik; Nadal, David et al. (2013) Innate immune responses against Epstein Barr virus infection. J Leukoc Biol 94:1185-90|
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