The main interest of our lab has been the molecular basis of the regulation of human natural killer (NK) cell function in the context of different stimuli and the contribution of activating and inhibitory receptors to intracellular signals that dictate NK cell reactivity. NK cells are lymphocytes with important functions that include defense against viral and parasitic infections, elimination of tumor cells, regulation of adaptive immunity through cytotoxicity and cytokine secretion, and stimulation of vascular remodeling in early pregnancy. Fundamental knowledge on the regulation of natural killer cells can be applied to study their function in diseases such as cancer and malaria.
Severe malaria caused by Plasmodium falciparum parasite infection kills approximately 280,000 young children every year. Resistance to malaria is dependent on antibodies that are acquired after years of exposure. We have shown that NK cells destroy P. falciparum-infected red blood cells in the presence of antibodies from adults that have acquired clinical immunity to malaria. The antibody-dependent cellular cytotoxicity (ADCC) response of NK cells that we measured in peripheral blood samples obtained from people living in a region of high malaria transmission was associated with greater resistance to disease. A more detailed examination of the composition and function of NK cells in people exposed to intense malaria transmission is needed. See more about the NIAID Malaria Research Program and the MRP Collaborative Research Fellowship Award.
There has been remarkable progress in the application of basic discoveries in immunology to clinical care of cancer patients. Immunotherapy has successfully eliminated otherwise incurable cancers. Cytotoxic T cells and NK cells have been engineered to express chimeric antigen receptors (CAR) that selectively target tumor cells for elimination. However, the limited information currently available on signal transduction by CARs is a concern. Furthermore, a limitation of NK cells for CAR expression is their control by dominant inhibitory receptors for HLA class I. We are engineering NK-tailored CARs that can overcome this inhibition. A significant advantage of our approach is that CAR-NK cells would remain under physiological regulation by inhibitory receptors until they encounter a tumor cell.
Dr. Long has a biochemistry degree from the ETH Zürich, and a Ph.D. in molecular biology from the University of Geneva, Switzerland. After postdoctoral research at the Carnegie Institution for Science and the National Cancer Institute, NIH, he returned to Geneva as a faculty member in the Department of Microbiology. There, he applied molecular approaches to isolate the first cDNA clones for MHC class II molecules. In 1983, he joined the Laboratory of Immunogenetics at the National Institute of Allergy and Infectious Diseases, NIH. While studying antigen presentation to CD4 T cells, he discovered new pathways for processing and MHC-II-restricted presentation of antigens from different cellular compartments. He became Senior Investigator and Head 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 function, after his team identified molecular clones for a family of NK cell inhibitory receptors called KIR that engage MHC class I molecules on healthy cells to prevent killing by NK cells. The discovery of the signaling basis for inhibition by these receptors was selected as a "Pillar of Immunology" by the Journal of Immunology. His laboratory has uncovered fundamental properties of NK cell activation for cytotoxicity, which requires engagement of synergistic pairs of coactivation receptors, and how they could be exploited to design chimeric antigen receptors (CAR) tailored for NK-dependent lysis of tumor cells. As part of the Malaria Research Program at NIAID, his group showed that NK cells lyse red blood cells infected by Plasmodium falciparum in the presence of antibodies isolated from plasma of individuals that live in an area of high malaria transmission. Among such individuals, those with a higher abundance of specialized NK cells with stronger responsiveness to an antibody-binding Fc receptor had better odds of becoming resistant to malaria. His lab is interested in NK cell functionality in people chronically infected by Plasmodium falciparum and how NK cells protect them against malaria.
- Zhuang X, Long EO. NK Cells Equipped With a Chimeric Antigen Receptor That Overcomes Inhibition by HLA Class I for Adoptive Transfer of CAR-NK Cells. Front Immunol. 2022;13:840844.
- Hart GT, Tran TM, Theorell J, Schlums H, Arora G, Rajagopalan S, Sangala ADJ, Welsh KJ, Traore B, Pierce SK, Crompton PD, Bryceson YT, Long EO. Adaptive NK cells in people exposed to Plasmodium falciparum correlate with protection from malaria. J Exp Med. 2019;216(6):1280-1290.
- Sim MJW, Rajagopalan S, Altmann DM, Boyton RJ, Sun PD, Long EO. Human NK cell receptor KIR2DS4 detects a conserved bacterial epitope presented by HLA-C. Proc Natl Acad Sci U S A. 2019;116(26):12964-12973.
- 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 Plasmodium falciparum 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.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
Microbiology and Infectious Diseases
This page was last updated on Sunday, August 14, 2022