In a prior study, von Andrian says, his group had noticed T cells within lymph nodes flit “like bumblebees” from one antigen-presenting dendritic cell (DC) to another. Now they have found that when antigens are scarce, it takes many hours for them to settle down and connect with DCs, the prelude to full activation.
To determine the rules governing this transition to a stationary phase, the authors injected foreign T cells and observed them in a lymph node directly behind the knee in mice. When they also injected foreign DCs carrying labeled antigen into the footpad, they could watch as T cells and DCs met in the lymph node.
They found that the more antigen in the environment, the less time a T cell spent flitting around before latching onto a DC. Using DCs with differing antigen density, they showed that T cells would rapidly settle down with low-antigen density DCs, as long as they had previously encountered high amounts of antigen before.
“It was the total dose exposure, not the dose on any one dendritic cell, that triggered the response,” von Andrian says. “The T cell has to make a binary decision, but antigen dose is an analogue signal, dependent on number and density. Somehow, the T cell is able to integrate that signal from its multiple encounters.” This feature would allow the T cell to respond when there is a lot of low-affinity antigen, as might occur during an infection. “A T cell can make an informed decision only by remembering how much antigen it has been exposed to. Now we must understand how it does so.”