Study Reveals a New Mechanism of Natural Killer Cell Activation

July 19, 2017
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Columbus, Ohio – Researchers have discovered a previously unknown mechanism that enables a certain type of immune cell to recognize and kill viral-infected cells.

The findings could have important implications for vaccines against infectious diseases, understanding and treating autoimmune diseases, preventing certain infusion reactions and improving immune therapy for cancer, the researchers say.

The study, led by researchers at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James), and published in the journal Immunity, focuses on immune cells called natural kill (NK) cells.

NK cells are well known for their ability to kill infected cells and cancer cells when those cells are coated with the antibody immunoglobulin G (IgG). Contact with the antibody on the cells activates an NK cell to release substances that kill the infected cell or cancer cell. That mechanism is called antibody-dependent cell-mediated cytotoxicity, or ADCC.

“Our study discovered a mechanism that enables NK cells to identify infected cells in a way that doesn’t involve the conventional antigen-antibody interaction,” says first author and co-corresponding author HongSheng Dai, PhD, a post-doctoral researcher at the OSUCCC – James. Dai was a 2014 Pelotonia Postdoctoral Research Fellow recipient. 

The new mechanism explains how NK cells can clear pathogens in the absence of pathogen-specific antibodies. The researchers call the new mechanism Fc-bridged cell-mediated cytotoxicity (FcBCC). Here is how it works.

Like all antibodies, IgG is shaped like a Y. The arms of the Y are called the Fab fragment, and they bind with an antigen. The stem of the Y is called the Fc fragment, and it binds with an NK cell or other immune cell.

Traditionally, it is thought that IgG antibodies require both the arms and the stem to activate NK cells, which is the case for ADCC.

“But many viruses and bacteria make proteins that bind with the trunk of the Y, with the Fc fragment, but the consequences of this were unknown,” says principal investigator Michael A. Caligiuri, MD, director of The Ohio State University Comprehensive Cancer Center and CEO of The James Cancer Hospital and Solove Research Institute.

“We discovered that just the Fc fragment alone of IgG can bridge certain pathogens and NK cells,” Caligiuri says. “This enables NK cells to clear pathogens or pathogen-infected cells in the absence of pathogen-specific antibodies.”

For example, when herpes virus type 1 (HSV1) infects a cell, it makes a protein that binds with the lower half of IgG molecules. At some point, the cell displays that protein on its surface, a signal that it is infected.

The study by Caligiuri, Dai and their collaborators shows that NK cells and many other immune cells have IgG on their surface. When the NK cell encounters a HSV1-infected cell, the viral protein displayed on the infected cell binds with the Fc portion of IgG that is displayed on the NK cell. When this bridge forms, it activates the NK cell to kill the infected cell.

“Identifying this previously unknown role of the lower half of IgG in immune responses opens up possibilities for its involvement in autoimmune diseases and cancer immunotherapy,” Caligiuri says.

Caligiuri also notes that it is highly likely that FcBCC at least partly explains how NK cells rapidly clear HSV1 oncolytic viruses when they are used to treat malignant glioma, and when they clear infection by other herpesviruses that encode Fc-binding proteins.

“Many pathogens produce proteins that bind with the Fc region of IgG, which leads us to believe that this mechanism may have broad implications in controlling infectious diseases,” Dai says.

Funding from the National Institutes of Health/National Cancer Institute (grants P01CA163205, P01CA095426, CA155521) and by a Pelotonia fellowship supported this research.

Other researchers involved in this study were Nathaniel Griffin, Chelsea Bolyard, Hsiaoyin Charlene Mao, Jianying Zhang, Balveen Kaur, Jianhua Yu, The Ohio State University; Timothy P. Cripe, Nationwide Children’s Hospital and The Ohio State University; Tadahiro Suenaga, Hisashi Arase, Osaka University, Osaka, Japan; Ichiro Nakano,University of Alabama at Birmingham; and E. A. Chiocca, Brigham and Women’s Hospital, Harvard Medical School.

Media Contact: Amanda Harper, director, Media Relations
Direct: 614-685-5420; central media office: 614-293-3737

Written by: Darrell E. Ward, associate director for Cancer Communications
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