'License To Kill' Enables Powerful Immune Attack Cells In Mice

This licensing process apparently helps reduce the chances that thecells will erroneously direct their firepower at the body's owntissues, according to researchers at Washington University School ofMedicine in St. Louis. The process is very different from otherpreviously identified ways that help immune cells distinguish invadersfrom self, and could have important implications for doctors strugglingto understand such issues as persistent viral infections and patients'responses to bone marrow transplants. The findings will appear in theAugust 4 issue of Nature.

The immune cells in question already evoked cinematic connectionssimply by virtue of one of their names: scientists commonly refer tothem as natural killer cells. The cells rapidly attack invaders and arecontinually generated in the bone marrow, leading to replacement of theentire population approximately once a week.

Scientists led by Wayne M. Yokoyama, M.D., the Sam J. Levin and AudreyLoew Levin Professor of Research in Arthritis, and professor ofmedicine and of pathology and immunology, discovered throughexperiments in mice that the arsenals of natural killer cells onlybecome fully armed after a receptor on their surfaces interacts with amolecule on the surfaces of other cells.

The molecular details of the process were so unusual that Yokoyama andhis colleagues found themselves struggling to develop terms to describeit to other immunologists.

"So many other terms that might have been appropriate--education,tolerance, instruction, selection--already have specialized meanings inimmunology that really aren't appropriate for this unique process we'vediscovered," says Yokoyama, who is a Howard Hughes Medical InstituteInvestigator and chief of the Division of Rheumatology at Barnes-JewishHospital. "Many of these terms refer to processes with a similaroutcome--improved ability to distinguish between self and non-self--butthis is a very different way of reaching that goal. So we came up withthe term licensing."

Their results include another ironic connection to the world of cinemaspies: the molecular details of the process feature a player who iscomparable to a double agent. Scientists have known for some time thatnatural killer cells have inhibitory receptors on their surfaces.

The natural killer cells' ability to attack is inhibited whenthese receptors encounter a molecule known as major hiscompatibilitycomplex (MHC) class I on the surface of other cells. MHC serves as akind of molecular I.D. badge, helping the natural killer cells todistinguish the self from an invader.

But Yokoyama's group found that the inhibitory receptors switch rolesduring licensing. Although the structure of the receptors is exactlythe same in immature natural killer cells, they act not as inhibitorsbut as enablers. In their studies, natural killer cells in mice becamemuch more capable of mounting attacks against invaders after they firstencountered the mouse version of MHC.

"The structure of these receptors on human natural killer cellsis different from the mouse version, but they have a similar function,"says lead author Sungjin Kim, Ph.D., research instructor inrheumatology. "We will be looking for a way to see if the human versionalso participates in some kind of licensing process."

The group's research was made possible by a unique mouse line createdby Ted H. Hansen, Ph.D., professor of pathology and immunology and ofgenetics. Mice normally have many different versions of the MHCmolecule, but Hansen created a line that makes only one. This wasessential to the ability of Yokoyama's group to test its hypothesis.

The new findings from Yokoyama's laboratory could explain some puzzlingoutcomes in the clinic, including why some patients with hepatitis Cinfections can be cured while others have a chronic infection for therest of their lives.

"This could be an important advance both conceptually and in terms ofclinical practice," Yokoyama says. "It could also help us match bonemarrow transplants in a way that increases the immune system's abilityto fight off a relapse of the leukemia."

Kim S, Poursine-Laurent J, Truscott SM, Lybarger L, Song Y-J, Yang L,French AR, Sunwoo1 JB, Lemieux S, Hansen TH, and Yokoyama WM. Licensingof natural killer cells by host MHC class I. Nature, August 4, 2005.

Funding from the Howard Hughes Medical Institute, the NationalInstitute of Allergy and Infectious Diseases, the Rheumatic DiseaseCore Center at Washington University, and the Barnes-Jewish HospitalFoundation supported this research.