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Researchers Offer a Detailed Look at Natural Killer Cells

Study Provides a New Framework for Understanding Immunity in Health and Disease

An NIAID-funded study has revealed a vast diversity of natural killer cells previously unrecognized in the human immune system. Natural killer (NK) cells are important for antiviral and antitumor responses, and these findings may have important implications for the development of new therapies for infection and cancer. The study appears in the October 23, 2013 issue of Science Translational Medicine.

illustration of an NK cell receptor

Inhibitory NK cell receptor (purple and light blue) binds to MHC-I (blue and red), an interaction that prevents immune responses against self.
Credit: NIAID


NK cells are important for immune surveillance, distinguishing foreign cells from healthy host cells, and killing virus-infected cells and tumor cells. NK cells are not identical, and subpopulations have different roles. The function of an NK cell is linked to the receptors expressed on its surface, which relay specific messages to the cell.

There are two types of NK receptors, activating and inhibitory. Activating receptors are needed for NK cells to respond to problems like infection and cancer. Inhibitory receptors are essential for NK cells to maintain self-tolerance—the prevention of an immune response against healthy cells in your body.

Prior to this study, the identification of NK cell subpopulations in people had been limited by technology. Cell types are typically sorted by fluorescence-based flow cytometry, a method where color-coded antibodies bind to receptors. This technique can generally identify up to 12 receptors on a single cell. Recently, new technology called mass cytometry, or cytometry by time-of-flight (CyTOF), has allowed for simultaneous identification of up to 40 receptors.

Results of Study

Using the new CyTOF technology, the researchers assessed a total of 28 unique receptors expressed in different combinations on the surface of human NK cells. Blood samples were examined from 12 unrelated people and 5 pairs of identical twins. Surprisingly, the researchers found that no phenotype, or combination of receptors, was dominant and no one population represented more than 7 percent of the total NK cell population. Overall, the researchers identified an unexpected and remarkable diversity of over 100,000 distinct NK cell phenotypes in the population, and predicted that a person may have between 6,000 to 30,000 phenotypes.

By comparing the NK cells of twins and unrelated people, the researchers inferred how the function of NK cells may be shaped by genetics versus the environment. The data suggest that the expression of inhibitory NK cell receptors is under genetic influence, whereas activating receptors are influenced by the environment. The researchers speculate that inhibitory receptors, which maintain self-tolerance, need stricter regulation through genetic control, while activating receptors must be more flexible in their response to environmental threats. However, more work must be done to clarify these relationships.

Significance and Next Steps

This detailed look at human NK cells shows an unexpected and vast diversity within this single immune cell type. Researchers aim to identify the specific function of each NK cell phenotype and understand how they are regulated. In the future, this knowledge might be used to design targeted NK cell-mediated therapies against infection, cancer, transplant rejection, and reproductive or autoimmune diseases.

The data from this study will be available in ImmPort, a comprehensive, open-access database that stores immunology data from NIAID-funded studies.


Horowitz A, Strauss-Albee DM, Leipold M, Kubo J, Nemat-Gorgani N, Dogan OC, Dekker CL, Mackey S, Maecker H, Swan GE, Davis MM, Norman PJ, Guethlein LA, Desai M, Parham P, Blish CA. Genetic and environmental determinants of human NK cell diversity revealed by mass cytometry. Science Translational Medicine (2013)​​

Last Updated October 23, 2013