Front-line Immune Cells Mature In Four Stages, Study Shows

The researchers found that natural killer (NK) cells, one of the body's front-line defenses against cancer and infections, mature from progenitor stem cells in four discrete stages. They also found that this happens in secondary lymphoid tissue such as tonsils and lymph glands.

Key discoveries made decades ago in animals and humans showed that the other two major types of immune cells in the body, T cells and B cells, developed in the thymus and bone marrow, respectively. However, the site and stages of human NK cell development have eluded investigators until now.

The findings advance the understanding of NK cells, which play a key role in triggering broader immune responses such as the body's permanent protection following vaccination. Understanding the secrets of NK cell development in humans could lead to new therapies for cancer, infection and for patients with immune deficiencies.

The study by researchers at the Ohio State University Comprehensive Cancer Center (OSUCCC) is published in the April 17 issue of the Journal of Experimental Medicine. Identification of the stem cell from which the human NK cell is derived was published by the OSUCCC research team last year in the journal Immunity.

“While there is a lot more work to do, this discovery unlocks another of Mother Nature's secrets,” says principal investigator Michael A. Caligiuri, director of the OSUCCC and the Division of Hematology-Oncology.

“Still, we believe it opens new doors to manipulating the human immune system to our benefit, and we're working on that right now,” says Caligiuri, who is also professor of internal medicine, of molecular virology, immunology and medical genetics and of veterinary biosciences.

“The findings will also boost NK-cell research,” says first author Aharon G. Freud, a physician who is a doctoral student in Caligiuri's laboratory. “The next step is to figure out why they develop in lymph tissue and whether patients with cancer have altered NK cell development.”

Scientists have known for some time that cells with a protein called CD34 on their surface can give rise to NK cells. They also knew that mature NK cells lack CD34. But how and where the CD34-bearing cells became mature NK cells was not understood.

For this study, Caligiuri, Freud and their collaborators analyzed tissues from more than 50 tonsils and 30 lymph nodes from the OSUCCC Tissue Procurement Shared Resource and from the National Disease Research Interchange.

Through a series of experiments, they identified additional protein markers, particularly one called CD117, that suggested that NK cells mature in four discrete stages in these tissues.

Ironically, a clue came 10 years ago, when Caligiuri discovered CD117 on mature NK cells. “NK cells were the only immune cell to express CD117, and CD117 is a stem-cell marker, so that told us there was a bridge between stem cells and NK cells.” Once we discovered where to look (in lymph tissue), it was just a matter of careful, diligent work.”

The researchers also isolated cells of each stage and showed that under the proper conditions, stage-1 progenitor cells matured into stage-2 NK cells, and that these cells matured into stage-3 cells and stage-4 cells, with the hallmarks and cell-killing capacity of mature NK cells.

The researchers are now working to gain a detailed understanding of stage-2 and stage-3 NK cells, including precisely where they mature within tonsils and lymph nodes and whether they play a role in immune responses or are just going through the maturation process.

Funding from the National Cancer Institute supported this research. Caligiuri is also the John L. Marakas Nationwide Insurance Enterprise Foundation Chair in Cancer Research.