Disparate Individual Fates Compose Robust CD8 ⁺ T Cell Immunity

Abstract

A core feature of protective T cell responses to infection is the robust expansion and diversification of naïve antigen-specific T cell populations into short-lived effector and long-lived memory subsets. By means of in vivo fate mapping, we found a striking variability of immune responses derived from individual CD8(+) T cells and show that robust acute and recall immunity requires the initial recruitment of multiple precursors. Unbiased mathematical modeling identifies the random integration of multiple differentiation and division events as the driving force behind this variability. Within this probabilistic framework, cell fate is specified along a linear developmental path that progresses from slowly proliferating long-lived to rapidly expanding short-lived subsets. These data provide insights into how complex biological systems implement stochastic processes to guarantee robust outcomes.