First passage times to T cell activation

Abstract: Effective recognition of foreign antigens by the adaptive immune system relies on T cells being activated by antigen-presenting cells (APCs) in lymph nodes. Here, diffusing T cells may encounter cognate APCs that present matching antigen fragments or non-cognate ones that do not; they are also subject to degradation. We develop a stochastic model in which T cell-APCs interact via a sequence of recognition steps, represented as a multistage Markov chain. T cells are successfully activated only if the terminal state associated with a cognate APC is reached. We compute the probability of successful activation in the presence of interfering non-cognate APCs, T cell degradation, and lymph node exit, and analyze the mean first-passage time to activation. We also incorporate a kinetic proofreading mechanism that enables state resetting, and show how this enhances specificity toward cognate APCs.