License to kill: development of killer T cells observable

November 22, 1999

New model could show how immune system is thwarted by HIV and cancer

BOSTON-November 22, 1999-Researchers at the Center for Blood Research and Harvard Medical School report in the November 23 Proceedings of the National Academy of Sciences the development of an animal model that literally illuminates one of the most dramatic and, until now, obscure events in the body: how the immune system turns immature T cells into specialized killer, or cytotoxic, T cells, capable of seeking out and destroying cells maimed by cancer and infection.

"Now, we have a model that makes it possible to look at a unique and important subset of cells; first to identify it and then analyze it in novel ways," says Ulrich von Andrian, MD, PhD, HMS associate professor of pathology. "This system might allow us to get a better understanding of what provides the T cells' license to kill," he says. Ultimately, the model could be used to clarify such diseases as cancer and AIDS. Some researchers have suspected that viruses and tumor cells may thwart the immune system by taking away T cells' license to kill-that is, by sabotaging the cellular machinery that enables them to attack unwanted cells.

"During the initial stages of an HIV infection, there are lots of cytotoxic T cells in the body but, for some reason, they are not able to contain the infection," says N. Manjunath, PhD, research fellow, and lead author of the study. "Is there a defect in these cells? Understanding normal differentiation with our new model, we might help answer this question."

One of the biggest obstacles to understanding this crucial transformation has been spotting members of this elite corps in large enough numbers to study them. Relatively rare-white blood cells in general number about one in one thousand cells in the bloodstream-T cells also move with the same velocity as other cells in the blood so they tend to get lost in the crush.

To flush them out, von Andrian, Manjunath, and their colleagues created a mouse in which immature T cells were equipped, by genetic means, with a green fluorescent tag. Normally, immature, or naive, T cells learn to identify bits of foreign invaders, called antigens, early on, but develop into fully effective killer T cells-complete with the cellular machinery to kill-only when they encounter actual infection. To coax the quiescent killer T cells into their fully effective state, the researchers infected the mice with a virus. Upon reaching full maturity, almost all of the cells lost their green tag-essentially revealing themselves by becoming invisible.

Why the green light goes out in the mature T cells is not clear but it could be a by-product of other changes occurring inside the differentiating T cells-perhaps the removal of factors that help to drive green fluorescent protein expression. Some or all of these factors may control other genes which need to be turned off in order for the killer T cell to differentiate. Identifying these factors and the genes they control will be "a milestone forward towards understanding how killer T cells develop," says Manjunath.

Harvard Medical School

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