Cruel and calculating, but it's your best friend

September 8, 2000

Daniel Davis of Imperial College, London, won this year's Pounds 2,000 THES/Oxford University Press Science Writing Prize with this account of how the body's natural killer cells work

"There is grandeur in this view of life, with its several powers, having been originally breathed by the Creator into a few forms or into one; and that whilst this planet has gone cycling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being evolved."

Charles Darwin

Of the endless forms evolved so far on our planet, yours could be the most beautiful. But beauty is not a useful quality in defending yourself against disease. The way your body defends itself against disease is more brilliant than anyone knows. Surprises are still around nearly every turn for researchers trying to understand the human immune system, and the battle in your blood.

Your body is a metropolis of cells; in fact a million million cells. That is five times more than all the stars in our galaxy. Every cell in you shares the same blueprint, yet, just like people living in a giant city, each cell has its own history, appearance and its own specific job. Some of your cells make up an army. The soldiers, your white blood cells, are continually fighting disease as necessarily and mechanically as your heartbeat. And, like any good army, your white blood cells have many different strategies for combating disease. Part of the first line of defence comes from your white blood cells called "natural killer" cells. It is these natural killer cells that are the subject of my research. In your defence, the mission of most immune blood cells is to seek and destroy anything foreign in your blood. They do this with the help of a molecule found on the surface of nearly all your cells, the MHC protein.

Molecules made inside every cell are continually being chopped up and the pieces put up for show by the MHC protein at the cell surface. In this way, the MHC protein is continually reporting at the surface of cells all the molecules the cell is currently making. The white blood cells, called T-cells, have receptors that survey all the molecules put up for show by the MHC protein. If anything looks odd, like a virus molecule, the T-cell knows that something foreign, such as a virus, lurks within that cell. The T-cell that spotted it gets switched on and then either kills the cell directly or sounds the alarm to summon other platoons of cells.

The MHC protein allows a continual surveillance by T-cells to check that only normal and healthy molecules are being made inside your cells. But viruses are not so easily caught. They can escape this surveillance operation by killing the MHC protein and not allowing any more reports to come out of the cell.

If the MHC protein were killed by a virus, there would be no more reporting of what is going on in the cell, and the T-cells would have nothing to look at any more. T-cells that try to spot foreign things presented by the MHC protein must be able to recognise a whole universe of possible foreign things. For any one foreign thing, only a few T-cells will be able to recognise it. Then it takes some time for these few T-cells to multiply enough to mount a reasonable attack. That is in part why it takes a few days for you to recover from an illness such as flu. But natural killer cells, which detect disease by noticing something is missing from the normal cell surface, can be ready in sufficient numbers to mount a deadly quick attack on the diseased cells.

Natural killer cells are too small to see with the naked eye; 100 cells laid out in a row would be 1mm long, but we can watch the cells checking out other cells under a microscope. If the natural killer cell stumbles across an abnormal cell it will kill it in about 10-15 minutes.

To kill the diseased cell, molecules are secreted from the natural killer cell that punch a hole in the membrane of the viral-infected or tumour cell, which will then either commit suicide or surrounding liquid can enter and force the cell to burst.

Videos of human natural killer cells surveying healthy cells show that the natural killer moves into contact with the suspect cell for about one minute before moving off if the suspect cell is healthy. So the "check for MHC protein" takes about a minute. What happens in this minute? This seems the pivotal time in which the natural killer cell decides whether the suspect cell is healthy or not. This is the key to understanding how this part of your immune system works. In fact, to understand and manipulate molecular recognition between cell surfaces is a central goal of research in molecular biology from immunology to neuroscience.

This perilous decision to kill or not kill depends on the MHC protein. What exactly is it?

Proteins are basically long chains of atoms, mostly carbon, with some nitrogen, hydrogen and oxygen. Like a string - but each string of protein folds up in a special shape. There are techniques available to determine the position of nearly every atom in a protein and hence see the shape of that protein. We are interested in the shape of proteins, because that may give us clues to what that protein does and how.

As an analogy, imagine yourself as an alien looking down at our planet trying to make sense of objects on Earth. Using your state-of-the-art alien telescope, you see a bridge and try to guess the function of this object from its structure. The structural beams of the bridge are arranged to support a platform going from one side to another. Similarly, the shape of the MHC protein is moulded around its function. There is a clear groove in the MHC protein surface that holds in place a sample molecule from inside the cell. A billion MHC proteins would fit on a pinhead.

But if it is so small, how can we see it on the surface of the cells? And really we want to see what happens to the MHC protein during the critical minute of contact between a natural killer cell and a cell it is surveying.

In 1955, two scientists reported to The Royal Society of London that cells isolated from a jellyfish glowed green when prodded. In 1962, scientists working on a small island in British Columbia, Canada found out that these jellyfish light organs contain two proteins, one that binds calcium and emits a blue light and the other that absorbs the blue light and emits the green glow. This second protein became known as "green fluorescent protein" or more commonly, GFP.

This discovery remained in obscurity for about 30 years, until the gene for the jellyfish GFP was known. By attaching the jellyfish protein to other human proteins, we can make any protein glow and see their whereabouts in cells. If we attach GFP to the MHC protein, we have a way of seeing the MHC by making it glow green. But to locate the MHC protein while natural killer cells are surveying other cells, we need a powerful microscope that can also image in three dimensions.

Also around 1955, Marvin Minsky, nowadays renowned for research in artificial intelligence at the Massachusetts Institute of Technology, wanted to image the brain in 3D to learn how brain cells connect together. A normal microscope magnifies the outside of an object, say a brain or an apple. But to image in 3D would mean the ability to see each plane of an object separately, for instance to see the connections inside a brain or to see the apple core. Minsky's idea was to simply add a pinhole before the eyepiece, which then collects light coming from only a single plane in the sample. Yet, as with the discovery of the jellyfish fluorescent protein, Minsky's invention remained in obscurity until it was independently reinvented many years later.

Nowadays, we can use a microscope system based on Minsky's principal that uses powerful lasers to scan over samples and photograph the contact between natural killer and suspect cells to a resolution of 1/10,000th of a millimetre and costing up to Pounds 200,000. So, we have a way to make the MHC protein visible and a powerful 3D microscope to see it. The green-glowing MHC protein can be seen to move from all over the surface of a healthy cell to cluster at the point of the contact by a potentially deadly natural killer cell. It is as if a cell is desperate to show to the natural killer cell that it has a healthy amount of MHC protein on its surface and its life should be spared.

But the real surprise was not just that the protein clustered in defence of the cell. Rather, using the power of the 3D microscope, an image slicing through the plane of the contact between the cells shows that the MHC protein organises into a ring shape. And in the centre of the ring lies another, adhesive molecule. This organisation of proteins at the contact between blood cells has been called the "immune synapse" by analogy to the synapse at which communication between neurones takes place.

Nobody predicted that proteins would organise into a pattern at contacts between immune cells. The technology to see proteins organised into patterns at contacts between cells had been available for years, but nobody thought to look. Immune synapses were first seen between T-cells and other cells in 1998 by scientists working in Denver, Colorado. And baffling us completely, the pattern of proteins at the contact between a natural killer cell and a suspect cell is the other way round from that between a T-cell and a suspect cell. At the T-cell immune synapse, a ring of adhesive molecule is formed around a patch of the MHC protein.

That is where the natural killer cells come in. They are there to check that the MHC protein is functioning normally by getting to the surface of cells and properly reporting on the molecules being made in the cell. They do this by having receptors that recognise a healthy presence of the MHC protein and switch off the natural killer cells' default alarm signal. So, while MHC proteins can trigger the killing by T-cells if, for example, they are presenting a foreign virus molecule, they also inhibit the killing by natural killer cells just by being there. In this way, the natural killer checks that the continual surveillance operation by the MHC protein goes smoothly. This strategy for detecting diseased cells - that is, to check for an error in the normal goings-on of a cell rather than directly detect something foreign - is called the "missing-self" hypothesis.

If a cell expresses a healthy amount of the correct MHC protein, the natural killer has a receptor to see that. The receptor then signals "stop" to prevent the natural killer cell from killing. If the MHC protein is missing, as in a tumour or viral-infected cell, the receptor on the natural killer cell has nothing to bind to. No stop signal is sent by the receptor and the natural killer cell destroys the diseased cell. Also, in case of a transplanted organ, the MHC protein from a different person may not fit the natural killer receptor and again the receptor does not see healthy MHC protein, no stop signal is sent and the transplanted cell may also get killed.

It leads to loads of exciting questions - how do immune synapses help in disease recognition? How do immune synapses form? Answers to such questions often come by investigating molecular details, such as why is it that zinc appears to be required for natural killer cells to form immune synapses? Only by understanding how the immune system works at this level of molecular detail can we design ways to enhance or suppress natural immune responses, including how to enhance the immune response against blood-borne cancers or suppress the autoimmune response in asthma. Pharmaceutical intervention of specific intercellular clustering may be of use therapeutically, for instance to enhance natural killers' destruction of HIV-infected or tumour cells. Rapid tests for intercellular protein clustering could be developed to screen candidate drugs.

It is obvious that we have a tremendous way to go in understanding how cells communicate and recognise disease. But we are in the middle of a scientific revolution that is transforming molecular biology into an engineering discipline; we can manipulate the shapes of protein molecules in cells in the same way we engineer buildings and bridges in our cities.

Still there are about 5,000 different proteins at the cell surface. In this essay we have mentioned just three of them that are involved in the way natural killer cells scan your bodies for disease cells. And even for those three proteins - the MHC protein, the natural killer cell receptor and an adhesive molecule - there are many unanswered questions: how do they form those patterns at the immune synapse and what are the cells saying to each other through the patterns? Our studies of cells are still in their infancy - just 165 years ago it was still being debated whether all living things were even made of cells.

Links: Daniel Davis's home page: on the 3D microscope: Gateway to movies of green fluorescent protein: Gateway to sites about fluorescence, microscopes, cell imaging and such:

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