Diffusive Information Loss Frustrates T Cell Sensing of Antigen Quality

T cells, the orchestrators of the adaptive immune response, mount selective attacks against foreign substances (antigens). Individual T cells discriminate between self-derived and foreign substances by monitoring the quality of interactions between substances and the T cells' receptors, as characterized, for example, by the rates at which a substance binds and debinds the receptors as well as the equilibrium constant of the interaction. Due to stochastic effects, signaling modules in T cells do not have perfect information about the quality of receptors' interactions, leading to a variety of consequences for network function.

In particular, an analysis of diffusion equations suggests that diffusive second messengers lose information about signal duration as they propagate through space. In the context of T cell receptor signaling, this means that signaling machinery must be clustered in sub-micron regions around engaged T cell receptors if the cell is to efficiently discriminate on the basis of debinding rates. This conclusion may provide a rationale for recent experimental observations showing that T cell signaling machinery is pre-clustered. It is important to note that the results rely on three key assumptions that are motivated, but still unresolved, by the literature: (1) the cell actually requires information about the debinding rate; (2) it utilizes a diffusive second messenger for that purpose; and (3) diffusive signals originating from different receptors or subsequent interactions of the same receptor can mix.