July 27, 1998 ST. LOUIS, Mo., July 24, 1998 -- A report in today's issue of Science helps answer a question that has had scientists scratching their heads: How do immune cells tailor their responses to invading microbes while ignoring the body's own cells?
The part of the cell that detects harmful organisms has to punch in a code before the cell will go on the offensive, the researchers have found. Punching in just part of the code is as useless as entering the wrong security code into a lock.
"People have been trying to identify the steps that occur in the resting cell and during activation, but previous methods failed to reveal this, so no one could make heads or tails of it," says lead researcher Paul M. Allen, Ph.D., the Robert L. Kroc Professor of Pathology at Washington University School of Medicine in St. Louis. "We tried a different approach, and an elegant solution to this question emerged."
One of Allen's graduate students, Ellen Neumeister Kersh, is the paper's lead author. Andrey S. Shaw, M.D., associate professor of pathology, also took part in the study, which was funded by the National Institutes of Health.
The researchers studied helper T cells, a key component of the cellular immune system. When the supply of these cells dwindles, as in AIDS patients, the consequences are dire.
Helper T cells patrol the body, checking for harmful microbes. Other parts of the immune system blow an invader's cover by posting fragments of its proteins on its surface or on the surface of a cell where it's hiding out. Helper cells read these fragments -- called antigens -- like cops checking out a license plate. If the plate is foreign, they make the appropriate response. They may kill the microbe directly, help a killer T-cell dispose of a virus-infected cell or stimulate immune cells that manufacture antibodies.
Helper cells use receptors on their surface to read antigenic displays. But instead of getting close enough to get a really good look, T cell receptors interact only weakly with antigens. Scientists therefore have wondered how the cells can respond so specifically to enormous numbers of antigens they've never seen before.
The T cell receptor is a large collection of proteins. Those that stick out from the cell read the antigen and prompt inner parts to activate the cell. Scientists have suspected for some time that the activating signal involves the addition of phosphate groups to two long receptor components called zeta chains. But how this occurs has not been known.
Each zeta chain protrudes into the cell and has six separate sites for phosphates. Moving away from the plasma membrane, the sites are numbered A1, A2, B1, B2, C1 and C3.
The researchers made six antibodies, each recognizing a different site -- but only if a phosphate was in place. "This allowed us to see when each site was phosphorylated and under what conditions," Allen says.
They discovered that the zeta chain has two phosphate groups when a helper cell is at rest. The phosphates are attached to sites B1 and C2. They also found that B2 can't acquire a phosphate unless A2 is phosphorylated. And C1 can't be phosphorylated until A1 is phosphorylated. Both A1 and A2 have to be phosphorylated before a phosphate group can be added to B2 and C1.
Therefore the six phosphates are added in a specific order. The code that unlocks the door is: B1, C2, A1, A2, B2, C1.
A helper cell becomes fully active only when all six phosphates are in place. But the two resting-state phosphates may prime the pump, Allen says.
The study suggests that punching in the security code may buy time to properly proofread the antigen, preventing the helper cell from making a hasty decision about whom to attack. "You must engage the receptor long enough to get all six phosphates on each zeta chain," Allen says. "Then the T cell says, 'All right, I've fulfilled the criteria, so now I can go ahead.' But if the antigen belongs to the host, the complete code wouldn't be entered, preventing T cells from attacking the body's own cells."
Why foreign antigens trigger full phosphorylation and self antigens don't is the next part of the puzzle to be solved.
The research has no immediate clinical applications. "But we need to understand how these complex receptors work before we can intervene in autoimmune disease," Allen says. "This knowledge also might help us find ways to switch on helper cells when we want to boost the fight against infectious disease."
Kersh EN, Shaw AS, Allen PM. Fidelity of T cell activation through multistep T cell receptor z phosphorylation. Science, July 24, 1998.
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