Timing consistency of T cell receptor activation in a stochastic model combining kinetic segregation and proofreading

T cell receptor signaling must operate reliably under tight time constraints. While assuming quite different mechanisms, two prominent models of T cell receptor activation, kinetic segregation and kinetic proofreading, both introduce a distinct time scale. However, a clear understanding of whether and how those characteristic times give rise to a consistent timing of T cell receptor activation in the presence of stochastic fluctuations has been lacking so far. Here, using a simulation approach capable of modeling molecular interactions between adjacent cell membranes, we explore a stochastic model that combines elements of kinetic segregation and proofreading. Our simulations suggest that the two mechanisms interoperate, thereby rendering the corresponding stochastic times biologically functional. Receptor activation relies on rare molecular events that are not well characterized by the mean of the underlying probability density function. Yet, a consistent timing of receptor activation can be ensured by a modest number of proofreading steps.