Traditionally, innate immune cells have been considered """"""""non-specific"""""""" and thought to respond identically when re-encountering the same pathogen. In a mouse model of CMV infection, we have shown that NK cells have several features that are normally attributed exclusively to the adaptive immune system. After infection with MCMV NK cells expressing the activating Ly49H receptor, which directly recognizes the MCMV m157 glycoprotein, undergo extensive proliferation. After control of the virus, the population of Ly49H+ NK cells contracts, but generates long-lived """"""""memory"""""""" NK cells capable of enhanced cytokine production and cytolytic activity upon secondary encounter with the pathogen. Additionally, we have shown that co-expression of inhibitory Ly49 receptors reactive with self-MHC class I ligands restrain the response of these Ly49H+ NK cells during viral infection, such that NK cells without a self-MHC class I inhibitory receptor dominate the immune response to MCMV. The evolutionary advantage of maintaining NK cells that lack self-MHC class I reactive inhibitory receptors might be to ensure optimal responses to viral infection, despite the potential risk of attacking healthy cells. The overall goal of this grant is to characterize the nature of """"""""memory"""""""" mouse NK cells using the MCMV model, to determine whether mouse NK cells are capable of generating """"""""memory"""""""" against other viruses, and finally, whether human NK cells specifically recognize human CMV and also possess traits similar to mouse """"""""memory"""""""" NK cells.
The specific aims are: 1) To characterize the molecular and functional characteristics of long- lived """"""""memory"""""""" mouse NK cells responding to mouse cytomegalovirus and to establish whether vaccination of NK cells is possible. 2) To determine whether mouse NK cells can specifically respond to viruses other than cytomegalovirus and acquire """"""""memory"""""""" traits. 3) To test the hypothesis that the CD94-NKG2C receptor on NK cells recognizes human cytomegalovirus, and that interaction of this receptor with its ligand leads to generation of """"""""memory"""""""" NK cells.

Public Health Relevance

Natural Killer (NK) cells are a type of white blood cell that kill tumors and virus-infected cells and protect the host from cancer and infectious diseases. Previously, NK cells were considered non-specific in their recognition of pathogens;however, in a mouse model we have shown that some NK cells can specifically recognize mouse cytomegalovirus and protect the host from lethal infection with this virus. In the proposed study, we will determine whether NK cells can be vaccinated to provide improved protection of the host against cytomegalovirus. We will also examine whether NK cells can also protect mice against influenza virus infection. In humans, 60% of the population is infected by human cytomegalovirus (HCMV), which in healthy individuals only causes mild, subclinical infection;however, is life-threatening in newborns and in immunocompromised individuals, including kidney transplant patients and AIDS patients. Therefore, we will also examine whether human NK cells specifically recognize HCMV and determine how NK cells recognize this pathogen.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Immunity and Host Defense (IHD)
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Miller, Lara R
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University of California San Francisco
Schools of Medicine
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Nabekura, Tsukasa; Lanier, Lewis L (2016) Activating Receptors for Self-MHC Class I Enhance Effector Functions and Memory Differentiation of NK Cells during Mouse Cytomegalovirus Infection. Immunity 45:74-82
Cerwenka, Adelheid; Lanier, Lewis L (2016) Natural killer cell memory in infection, inflammation and cancer. Nat Rev Immunol 16:112-23
Lam, Viola C; Lanier, Lewis L (2016) NK cells in host responses to viral infections. Curr Opin Immunol 44:43-51
Guan, Zhonghui; Kuhn, Julia A; Wang, Xidao et al. (2016) Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat Neurosci 19:94-101
Hendricks, Deborah W; Min-Oo, Gundula; Lanier, Lewis L (2016) Sweet Is the Memory of Past Troubles: NK Cells Remember. Curr Top Microbiol Immunol 395:147-71
Nabekura, Tsukasa; Lanier, Lewis L (2016) Tracking the fate of antigen-specific versus cytokine-activated natural killer cells after cytomegalovirus infection. J Exp Med 213:2745-2758
Morvan, Maelig G; Lanier, Lewis L (2016) NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer 16:7-19
Madera, Sharline; Rapp, Moritz; Firth, Matthew A et al. (2016) Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide. J Exp Med 213:225-33
Nabekura, Tsukasa; Girard, Jean-Philippe; Lanier, Lewis L (2015) IL-33 receptor ST2 amplifies the expansion of NK cells and enhances host defense during mouse cytomegalovirus infection. J Immunol 194:5948-52
Kamimura, Yosuke; Lanier, Lewis L (2015) Homeostatic control of memory cell progenitors in the natural killer cell lineage. Cell Rep 10:280-91

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