Recent studies have demonstrated that Natural killer (NK) cells and possibly other innate cells can remember prior encounters with pathogens. The central focus of the project is to further our knowledge of how activating NK receptors (NKR) can drive the expansion, differentiation, and generation of immunological memory. The concept that NK cells can acquire immunological memory and mediate enhanced responses upon re- encountering pathogens provides a new paradigm that might be exploited in the therapeutic treatment of infectious diseases and cancer. The objective of aim 1 is to determine whether immunological memory in T cells can be generated and maintained by the same activating NKR that we have demonstrated are capable of inducing memory in NK cells. T cells frequently acquire expression of NKR during their differentiation, and the proposed studies will allow us to directly compare the immunological memory driven by a NKR versus the TcR in the same T cell. Further, it will allow us to directly compare memory driven by the same activating NKR in T cells versus NK cells in the same host.
In aim 2, we have developed a new tamoxifen-induced NK cell specific reporter mouse model to follow the fate of memory NK cells in situ following immune challenges with pathogens or tumors. This has never been possible previously, without the use of adoptive NK cell transfer procedures.
Aim 3 also addresses an important aspect of immunological memory, focusing of the contribution of a well-characterized activating NKR, the CD16 Fc receptor. We will investigate if signals through CD16 can drive or augment the generation of immunological memory in NK cells. This is important because of its implications in the immunotherapeutic use of antibodies in cancer patients that eliminate tumors by antibody- dependent cellular cytotoxicity. Collectively, all aims address the central question of immunological memory driven by activating NKR. Upon successful completion of the proposed studies, we will have new insights into the role of activating NKR on the TcR-dependent adaptive responses and TcR-independent innate responses of memory T cells, will provide the scientific community with a new NK cell reporter mouse that can be used to track the fate of memory NK cells after immunological challenges and inducibly ablate genes in mature NK cells, and determine whether the activating CD16 Fc receptor on NK cells is capable of inducing immunological memory and generating more potent NK cells that provide superior ADCC function in infectious diseases and cancer. Overall, these studies will advance our knowledge of an expanding paradigm of immunological memory driven by innate immune receptors.

Public Health Relevance

Natural Killer (NK) cells are a type of white blood cell that provides defense against certain microbial infections and cancer. Recently, we have demonstrated that NK cells can remember past encounters with viruses and function more efficiently upon subsequent infections. The goal of this project is to understand how NK cell immunological memory is generated and contributes to host defense against pathogens and cancer.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Immunity and Host Defense (IHD)
Program Officer
Lapham, Cheryl K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Méndez-Lagares, Gema; Lu, Ding; Chen, Connie et al. (2018) Memory T Cell Proliferation before Hepatitis C Virus Therapy Predicts Antiviral Immune Responses and Treatment Success. J Immunol 200:1124-1132
Nabekura, Tsukasa; Chen, Zhiying; Schroeder, Casey et al. (2018) Crk Adaptor Proteins Regulate NK Cell Expansion and Differentiation during Mouse Cytomegalovirus Infection. J Immunol 200:3420-3428
Sun, Joseph C; Lanier, Lewis L (2018) Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? NK Cell Memory and Immunization Strategies against Infectious Diseases and Cancer. Cold Spring Harb Perspect Biol 10:
Jensen, Helle; Potempa, Marc; Gotthardt, Dagmar et al. (2017) Cutting Edge: IL-2-Induced Expression of the Amino Acid Transporters SLC1A5 and CD98 Is a Prerequisite for NKG2D-Mediated Activation of Human NK Cells. J Immunol 199:1967-1972
Nabekura, Tsukasa; Gotthardt, Dagmar; Niizuma, Kouta et al. (2017) Cutting Edge: NKG2D Signaling Enhances NK Cell Responses but Alone Is Insufficient To Drive Expansion during Mouse Cytomegalovirus Infection. J Immunol 199:1567-1571
Jensen, Helle; Chen, Shih-Yu; Folkersen, Lasse et al. (2017) EBI3 regulates the NK cell response to mouse cytomegalovirus infection. Proc Natl Acad Sci U S A 114:1625-1630
Mukherjee, Sayak; Stewart, David; Stewart, William et al. (2017) Connecting the dots across time: reconstruction of single-cell signalling trajectories using time-stamped data. R Soc Open Sci 4:170811
Mukherjee, Sayak; Jensen, Helle; Stewart, William et al. (2017) In silico modeling identifies CD45 as a regulator of IL-2 synergy in the NKG2D-mediated activation of immature human NK cells. Sci Signal 10:
Lam, Viola C; Lanier, Lewis L (2017) NK cells in host responses to viral infections. Curr Opin Immunol 44:43-51
Crome, Sarah Q; Nguyen, Linh T; Lopez-Verges, Sandra et al. (2017) A distinct innate lymphoid cell population regulates tumor-associated T cells. Nat Med 23:368-375

Showing the most recent 10 out of 105 publications