Clues to the Maturation of Natural Killer Cells

Abstract

Scientists in The Ohio State University Comprehensive Cancer Center have made a paradigm-shifting discovery that sheds new light upon the growth and development of human natural killer (NK) cells, powerful but somewhat mysterious denizens of the body's immune system that are the first line of defense against cancer and infectious diseases.

Scientists have believed for years that human NK cells are generated in bone marrow, but Dr. Michael Caligiuri, director of the OSU Comprehensive Cancer Center and the senior author of the study, says research in his laboratory shows that the precursors to NK cells are actually found in cellular nurseries deep inside the body's lymph nodes.

The findings, appearing in the March 22 issue of the journal Immunity, may offer clinicians new direction in determining how to manipulate this cell type in enhancing immune responses to cancer.

"This study is fundamentally about understanding the immune system more fully so we can help patients," says Caligiuri.

A major arm of the body's defense system is made up of lymphocytes, cells that fall broadly into three categories - T cells, B cells and NK cells.

Although all lymphocytes stem from a common source - progenitor cells in the bone marrow - they take different paths in developing into full-fighters in the immune system. For example, cells destined to become T cells, sophisticated and highly focused killer cells, are released into the bloodstream and migrate to the thymus where they learn their role. In contrast, B cells, which make antibodies, remain and mature in the bone marrow. Until now, scientists thought NK cells did the same.

But Caligiuri, working with Aharon Freud, the lead author of the study, a doctoral candidate in the OSU medical scientist program and a member of Caligiuri's laboratory, had noted other work showing that mice lacking lymph nodes also lacked NK cells. In addition, in earlier research in Caligiuri's laboratory, scientists had identified two distinct subsets of human NK cells (referred to as CD56 bright and CD56 dim cells) and they observed that the bright subset appeared much more frequently in lymph nodes than in bone marrow or circulating blood.

In other words, they had a hunch traditional thinking about the origin of human NK cells might be wrong.

In building a case to support their beliefs, they first identified the NK precursor cell, then, they measured the number of the precursors in different parts of the body. Through flow cytometry, they discovered that while NK precursors make up about 1 percent of bone marrow progenitor cells and 6 percent of circulating blood progenitor cells, they comprise virtually all of the progenitor cells found in lymph nodes.

Interestingly, Dr. Gerard Nuovo, a pathologist and co-author of the study, discovered that these novel NK precursor cells are not randomly strewn throughout the lymph nodes, but rather localized near special sites called parafollicular regions, rich in T cells and NK bright cells.

"We thought this was pretty interesting because we know that in order for these NK precursor cells to grow and differentiate, they need one of two cytokines, interleukin-2 or interleukin-15," says Freud. "So it may not be coincidental that two types of immune cells that make those substances - T cells and dendritic cells - just happen to reside in lymph nodes, too."

Freud also makes the provocative observation that lymph nodes, while full of CD56 bright cells, are significantly lacking in their counterparts, the CD56 dim cells.

"Our next goal is to determine if there is some developmental continuum at work here, supporting the notion that CD56 bright cells are really just immature CD56 cells," he adds.

"This study raises almost as many questions as it answers," says Caligiuri. "Finding these nursery sites of NK cells is just the first step. We feel this is the first solid evidence supporting a new model of NK cell development, but we also know that more work needs to be done to fill in some gaps."

Still, the findings appear to offer important new information about NK killer cells that may ultimately be helpful in designing more effective treatments for cancer and other diseases says Caligiuri. "NK cells are the minutemen' of the defense system - the first to respond to an attack. The more we know about them, the more we can help them do their work. In cancer, as in other diseases, the sooner you intervene, the better."

Caligiuri holds the J.L. Marakas Nationwide Insurance Enterprise Foundation Chair in Cancer Research at The Ohio State University.

Grants from the National Cancer Institute supported the project.

Additional colleagues from Ohio State who contributed to the study include Dr. Amy Ferketich, Martin Guimond and Robert Baiocchi; Brian Becknell and Sameek Roychowdhury from the medical scientist and intergrated biomedical science programs; and Hsiaoyin Mao, Tiffany Hughes, Trent Marburger and John Sung from Human Cancer Genetics.

The Ohio State University Comprehensive Cancer Center is a network of interdisciplinary research programs with over 200 investigators in 13 colleges across the OSU campus, the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and Children's Hospital, in Columbus. OSUCCC members conduct research on the prevention, detection, diagnosis and treatment of cancer, generating over $95 million annually in external funding.