Nobel prize honors insight into immunity.

Microscopic hit men roam the blood of humans and other animals. These single-minded killers, white blood cells called cytotoxic T cells, normally destroy only cells infected by viruses.

This year's Nobel Prize in Physiology or Medicine honors two scientists, Peter C. Doherty of St. Jude's Children's Research Hospital in Memphis and Rolf M.

Zinkernagel of the University of Zurich, whose fundamental discovery helped explain how these T cells recognize the targets they're assigned to kill.

The researchers were working at the John Curtin School of Medical Research in Canberra, Australia, in the early 1970s when they began to study how genetic variability influences the response of cytotoxic T cells.

The duo infected mice with a virus to obtain T cells that would kill the rodents' virus-infected cells. However, the T cells failed to kill infected cells from another strain of mice. This distinction, the two concluded, stemmed from the different cell surface proteins of each strain.

All mouse cells, and all human cells, carry surface proteins encoded by genes from the so-called major histocompatibility complex (MHC). But MHC genes vary so tremendously that the set of MHC proteins on an animal's cells serves as a molecular identification card. At the time of Doherty and Zinkernagel's work, researchers had already discovered that differences in MHC proteins could cause rejection of organs transplanted between unrelated people.

"Everybody knew these were important molecules, but nobody understood how the molecules were working in the immune system," says Ronald H. Schwartz of the National Institute of Allergy and Infectious Diseases in Bethesda, Md.

Doherty and Zinkernagel offered a compelling theory about the role of MHC proteins. They argued that before cytotoxic T cells kill an infected cell, they recognize both a piece of virus and an MHC protein characteristic of the animal. The immune cells of the first mouse strain ignored infected cells of the second strain because the strains' MHC proteins differed.

"The whole field was in a mess. We were very confused about what T cells were up to," recalls Phillipa Marrack of the National Jewish Center for Immunology and Respiratory Medicine in Denver. "It wasn't until they made the observation that the T cell somehow has to recognize the two [signals] at the same time that the whole thing made sense."

More recent research has illuminated how this dual recognition occurs.

Infected cells chop up viruses inside them and attach the viral pieces to MHC proteins. The cells then transport the combination to the cell surface so that cytotoxic T cells can have access to them. The T cells have surface proteins, called T cell receptors, that simultaneously recognize a viral component and an MHC protein.

Doherty notes that investigators are now using cytotoxic T cells to rid bone marrow transplants of viral infections and are designing vaccines, including those for AIDS, to generate these virus-killing cells. - J. Travis