Philippa Marrack is an immunologist supported by the Howard Hughes Medical Institute in the Department of Medicine at the National Jewish Medical and Research Center in Denver, Colo. In 1994, Marrack and her husband, John W. Kappler, won the prestigious Louisa Gross Horwitz Prize awarded by Columbia University. Here is her reply.

The body has many ways of recognizing invaders. Some of these are probably evolutionarily very old and inherited from our invertebrate ancestors. For example, the body recognizes chemical structures that are made by bacteria and quite different from chemicals made by higher organisms. These chemical structures include the special carbohydrates (sugars) and lipids that surround bacteria and peptides, such as the amino acid formyl methionine, which bacteria put at the beginning of all of their proteins.

When the body detects these special chemical structures, it activates several processes that lead to the destruction of the bacterium. These processes include increased movement of blood cells to the place where the invader has entered the body, increased phagocytosis (eating) by blood cells and activation of enzymes in the blood that can create holes in bacteria and hence destroy them.

Image: University of Virginia

KILLER T CELL binds to a receptor on the surface of a cell that is infected with a virus, causing the cell to be destroyed.

Vertebrates such as mice and men have evolved additional ways of recognizing invaders. These mechanisms use antibody molecules on blood cells called B cells and ab (alpha beta) or gd (gamma delta) receptors on blood cells called T cells. These receptors are created by a rearrangement of genes during the development of T and B cells.

For example, the a chain of the ab T cell receptor is a single polypeptide made up of three different segments: Va, Ja and Ca. There is only one Ca gene, but there are about 50 Va and 50 Ja genes. As a T cell develops, it randomly chooses one of the 50 Va genes and moves it next to one of the 50 Ja genes. Often random nucleotides (bits of DNA) are subtracted or added to the point at which the Va gene lies next to the Ja gene.

Hence T cells can create at least 50 2, or 2,500, different genes on the DNA "a" chain, and in fact, because of the random nucleotides, the number is probably much larger. Similar processes lead to the rearranged genes which code for T cell receptor "b" chain genes, and also to T cell receptor g and d genes and antibody genes.

Because of these rearrangements, each of the approximately 1012 B cells and 1012 T cells in a human being has a different receptor on its surface. These B and T cells exist within the blood and lymphatic system of the body in what is called a resting state--that is, they are not doing anything detectable. However, when a B or T cell encounters an invader that can bind to its receptor, the cell divides many times and so creates lots of daughter cells. Each bears receptors that are the same as, or very similar to, those of the parent. Hence, contact with the invader creates from a few B and T cells many more that can react with the invader.

During this division the T and B cells also create so-called effector and memory cells. Effector cells act to get rid of the invader. For example, effector B cells, called plasma cells, secrete antibody molecules that bind to invading bacteria and viruses and help eliminate them from the body. One type of effector T cell, called a cytotoxic T cell, kills virus infected cells and thus prevents its spread. The memory cells survive to protect their host against further infections by the same invader.

B cells bearing antibodies and T cells bearing ab or gd receptors recognize the appearance of an invader in the body in different ways. B cell antibodies bind to the invading particle, such as a bacterium, in the form in which it enters the body. The ab receptor-bearing T cells do not bind the invader directly. Instead, they bind to peptide fragments made from the invader's proteins. These fragments are created inside other cells. For example, viruses must invade host cells to increase in number. There, they produce their own proteins and copies of their genes.

Some of the viral proteins, however, are chewed up into peptides by the invaded cells. These peptides bind to proteins called major histocompatibility complex (MHC) proteins. It is this combination of viral peptide and MHC protein that the ab T cell receptors recognize.

It is still not certain how gd receptor bearing T cells recognize invaders. One hypothesis is that they react with damaged cells, that is, rather than recognizing the invader directly, they recognize the damage that the invader has done to the host.

These different ways of homing in on something foreign that has arrived in the body are thought to act as backups for each other. The old systems react with chemicals that are very different between bacteria and mammals. B cells and their antibodies react directly with invading organisms and help rid the body of them. The ab T cells react only with fragments of invading organisms associated with cells. These cells therefore help the body reject organisms, such as viruses or tuberculosis bacteria, that exist inside cells. The ab T cells are also good at reacting with other cells of the immune system, such as B cells. And the gd T cells react with damaged host cells.

Although an invading organism may evolve so that it can avoid one of these methods of recognition, it is almost impossible for an invader to avoid all types of immunity. Therefore, higher vertebrates are well protected against most organisms.