The immune system responds to viral infections by introducing a complex interplay of immune cells and factors, whose goal is to eliminate the intruding pathogen. One such effector cell in the antiviral response is the natural killer (NK) cell, which secretes inflammatory cytokines and directly kills infected cells. The long-term goals of my research are to understand the role of activating and inhibitory receptors in the NK cell response against viral infection. Using cellular and molecular biological techniques, we will study how the signals lymphocytes receive during infection influences the development of adaptive immune memory and the ability of immunized hosts to respond against subsequent pathogen exposure. Elucidating the signals that activate and regulate NK cells will have broad implications in our fight against infectious diseases and cancer. My K99/R00 research plan details my immediate and long-term career goals in understanding the cellular and molecular mechanisms behind immunological memory. My immediate goals are to begin defining the early cytokine signals NK cells receive that drive their proliferation and memory cell formation. Incorporating viral infection models, cytokine receptor knockout mice, and NK cell-deficient mouse models, we will begin addressing the environmental factors that drive proliferation and memory cell formation in NK cells (Aims 1 and 2). Furthermore, we will engineer pathogens expressing specific antigens in order to determine how to vaccinate via the NK cell compartment (Aim 3). Altogether, this research effort will have important clinical relevance and will influence immunization strategies against viruses. My long-term goals after becoming an assistant professor include forming a research program to explore the development of NK cells, NK cell responses against infection, and NK cell memory maintenance. The broad goals of my future research program will have implications in both the understanding of basic NK cell biology as well as in vaccine development against cancer and infectious disease. By gaining a better understanding of how this arm of the immune system specifically attacks virally-infected and cancerous cells, but not healthy cells, we will be able to develop more effective preventative and therapeutic approaches in the battle against infectious diseases and cancer.
The focus of my research has been aimed at defining the signals that natural killer (NK) cells require to mount an effective immune response against pathogens, and exploring the regulatory mechanisms keeping NK cells in check, thereby safeguarding against autoimmunity. This work will have broad implications in vaccine development against cancer and infectious disease, and in the prevention of autoimmunity. By gaining a better understanding of how cells of the immune system specifically attack virally-infected and cancerous cells, but not healthy cells, we will be able to develop more effective preventative and therapeutic approaches in the battle against infectious diseases and cancer.
| Johnson, Lexus R; Weizman, Orr-El; Rapp, Moritz et al. (2016) Epitope-Specific Vaccination Limits Clonal Expansion of Heterologous Naive T Cells during Viral Challenge. Cell Rep 17:636-644 |
| Adams, Nicholas M; O'Sullivan, Timothy E; Geary, Clair D et al. (2016) NK Cell Responses Redefine Immunological Memory. J Immunol 197:2963-2970 |
| Geiger, Theresa L; Sun, Joseph C (2016) Development and maturation of natural killer cells. Curr Opin Immunol 39:82-9 |
| 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 |
| O'Sullivan, Timothy E; Johnson, Lexus R; Kang, Helen H et al. (2015) BNIP3- and BNIP3L-Mediated Mitophagy Promotes the Generation of Natural Killer Cell Memory. Immunity 43:331-42 |
| O'Sullivan, Timothy E; Sun, Joseph C; Lanier, Lewis L (2015) Natural Killer Cell Memory. Immunity 43:634-45 |
| O'Sullivan, Timothy E; Sun, Joseph C (2015) Generation of Natural Killer Cell Memory during Viral Infection. J Innate Immun 7:557-62 |
| Lu, Li-Fan; Gasteiger, Georg; Yu, I-Shing et al. (2015) A Single miRNA-mRNA Interaction Affects the Immune Response in a Context- and Cell-Type-Specific Manner. Immunity 43:52-64 |
| Beaulieu, Aimee M; Zawislak, Carolyn L; Nakayama, Toshinori et al. (2014) The transcription factor Zbtb32 controls the proliferative burst of virus-specific natural killer cells responding to infection. Nat Immunol 15:546-53 |
| Sun, Joseph C; Ugolini, Sophie; Vivier, Eric (2014) Immunological memory within the innate immune system. EMBO J 33:1295-303 |
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