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
Contact: Linda Sage
Washington University School of Medicine