The main goal of the section is to understand the molecular and biochemical basis for the regulation of natural killer (NK) cell activation in the context of different stimuli and to define the contribution of activating and inhibitory receptors to intracellular signals that dictate NK cell reactivity. NK cells are lymphocytes with important functions that include control of viral and parasitic infections, tumor surveillance, regulation of adaptive immunity through cytotoxicity and cytokine secretion, and stimulation of vascular remodeling in early pregnancy. Specificity in NK cell responses is achieved by a complex integration of signals from germ line-encoded activating and inhibitory receptors.
We have used NK cells as a model to study fundamental processes in cell biology. Some of our basic discoveries have been successfully translated into clinical applications. Our identification of human killer-cell Ig-like receptors (KIR) and their HLA class I specificities has been applied to the development of new protocols for hematopoietic stem cell transplantation that favor graft-versus-leukemia activity over graft-versus-host disease. The resounding success of cancer immunotherapy that targets “checkpoint inhibitors,” such as PD-1, highlights the need to decode the interplay between inhibitory and activating signals to promote anti-tumor cytotoxic responses. Our work on how inhibitory KIR recruits tyrosine phosphatase SHP-1 to deliver a dominant inhibitory signal that overrides activation signals has served as the prototype for signaling by inhibitory receptors of the ITIM family.
We integrate proteomics and imaging approaches with cellular and biochemical techniques to understand how NK cell activity is regulated. In doing so, we have gained insights into regulation of cellular functions by inhibitory receptors, signaling by integrin LFA-1 for adhesion and granule polarization, and the dynamics of NK cell immunological synapses. Following on our earlier work, which showed that zinc ions (Zn2+) are required for the function of an inhibitory KIR, we have discovered that Zn2+ induces polymerization of inhibitory receptor into filaments.
A recent addition to our research is the study of NK cells in malaria. In a collaborative effort with the Malaria Research Program at NIAID, we are dissecting the response of NK cells to Plasmodium parasite infection at both the liver stage and the blood stage and how it may contribute to protective immunity. We are studying human NK cells from a cohort of individuals living in a malaria-endemic area and liver NK cells in mice infected with Plasmodium sporozoites. See more about the Malaria Research Program.
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Dr. Long has a biochemistry degree from the ETH Zürich, Switzerland, spent a year as a postbac at the MRC Department of Molecular Genetics, University of Edinburgh, and obtained a Ph.D. in biology from the University of Geneva, Switzerland. After postdoctoral research at the department of embryology, Carnegie Institution, Baltimore, and at the National Cancer Institute, National Institutes of Health, he returned to Geneva as a faculty member in the department of microbiology at the medical school. There, he began to apply molecular approaches to study MHC class II molecules and processing pathways for antigen presentation to CD4 T cells. He then joined the Laboratory of Immunogenetics, NIAID, where he became a senior investigator and chief of the Molecular and Cellular Immunology Section in 1988. In the mid-90’s, his main interest turned to the regulation of natural killer (NK) cell activation, when his team identified molecular clones for the inhibitory killer cell Ig-like receptors (KIR) and the signaling basis for inhibition.
Sumati Rajagopalan, Ph.D., Staff Scientist
Mary E. Peterson, Biologist
Kaveh Abdi, Biologist
Olga M. Antón, Postdoctoral Fellow
Geoffrey Hart, Postdoctoral Fellow
Gunjan Arora, Postdoctoral Fellow
Malcolm Sim, Postdoctoral Fellow
The Molecular and Cellular Immunology Section has joined the newly created Malaria Research Program at NIAID—October 2015.
Kumar S, Rajagopalan S, Sarkar P, Dorward DW, Peterson ME, Liao H-S, Guillermier C, Steinhauser ML, Vogel SS, Long EO. Zinc-induced polymerization of killer-cell Ig-like receptor into filaments promotes its inhibitory function at cytotoxic immunological synapses. Mol Cell. 2016 Apr 7;62(1):21-33.
Anton OM, Vielkin S, Peterson ME, Tagaya Y, Long EO. NK cell proliferation induced by IL-15 transpresentation is negatively regulated by inhibitory receptors. J Immunol. 2015 Nov 15;195(10):4810-21.
Zhang M, March ME, Lane WS, Long EO. A signaling network stimulated by β2 integrin promotes the polarization of lytic granules in cytotoxic cells. Sci Signal. 2014 Oct 7;7(346):ra96.
Long EO, Kim HS, Liu D, Peterson ME, Rajagopalan S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol. 2013 Mar 21;31:227-58.
Rajagopalan S, Long EO. Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling. Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20596-601.
Liu D, Peterson ME, Long EO. The adaptor protein Crk controls activation and inhibition of natural killer cells. Immunity. 2012 Apr 20;36(4):600-11.
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We are always interested in recruiting bright and motivated young scientists. If you think you fit the description, send us an application. Experience in imaging, cell biology, proteomics, and bioinformatics would be a plus.
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Fellowships will be awarded annually to a limited number of top applicants who aspire to improve our understanding of the biology, host-pathogen interactions, and transmission of malaria parasites.
See Malaria Research Program.
Students interested in a Ph.D. program have the option of joining one of the NIH Graduate Partnership Programs with academic institutions including the following, among others:
See more information on available partnerships in the NIH Graduate Partnerships Program (GPP).
Submit an application online at Postbaccalaureate Intramural Research Training Award (Postbac IRTA/CRTA).
Rajagopalan S, Moyle MW, Joosten I, Long EO. DNA-PKcs controls an endosomal signaling pathway for a proinflammatory response by natural killer cells. Sci Signal. 2010 Feb 23;3(110):ra14.
Martinez E, Brzostowski JA, Long EO,* Gross CC*. Cutting edge: NKG2D-dependent cytotoxicity is controlled by ligand distribution in the target cell membrane. J Immunol. 2010 Sep 1;185(5):2918-26.
Rajagopalan S, Lee EC, DuPrie ML, Long EO. TNFR-associated factor 6 and TGF-β-activated kinase 1 control signals for a senescence response by an endosomal NK cell receptor. J Immunol. 2014 Jan 15;192(2):714-21.
Last Updated April 12, 2016