Eric O. Long, Ph.D.
Molecular and Cellular Immunology Section
TW2 Building, Room 201E
12441 Parklawn Drive
Rockville, MD 20852
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.
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.
Arora G, Hart GT, Manzella-Lapeira J, Doritchamou JY, Narum DL, Thomas LM, Brzostowski J, Rajagopalan S, Doumbo OK, Traore B, Miller LH, Pierce SK, Duffy PE, Crompton PD, Desai SA, Long EO. NK cells inhibit <i>Plasmodium falciparum</i> growth in red blood cells via antibody-dependent cellular cytotoxicity. Elife. 2018;7.
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;31:227-58.
Kim HS, Long EO. Complementary phosphorylation sites in the adaptor protein SLP-76 promote synergistic activation of natural killer cells. Sci Signal. 2012;5(232):ra49.
Liu D, Peterson ME, Long EO. The adaptor protein Crk controls activation and inhibition of natural killer cells. Immunity. 2012;36(4):600-11.
Kim HS, Das A, Gross CC, Bryceson YT, Long EO. Synergistic signals for natural cytotoxicity are required to overcome inhibition by c-Cbl ubiquitin ligase. Immunity. 2010;32(2):175-86.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
This page was last updated on August 30th, 2018