Environmental cues dictate the fate of individual CD8+ T cells responding to infection.

Many studies have examined pathways controlling effector T cell differentiation, but less is known about the fate of individual CD8+ T cells during infection. Here, we examine the antiviral and antibacterial responses of single CD8+ T cells from the polyclonal repertoire. The progeny of naive clonal CD8+ T cells displayed unique profiles of differentiation based on extrinsic pathogen-induced environmental cues, with some clones demonstrating extreme bias toward a single developmental pathway. Moreover, even within the same animal, a single naive CD8+ T cell exhibited distinct fates that were controlled by tissue-specific events. However, memory CD8+ T cells relied on intrinsic factors to control differentiation upon challenge. Our results demonstrate that stochastic and instructive events differentially contribute to shaping the primary and secondary CD8+ T cell response and provide insight into the underlying forces that drive effector differentiation and protective memory formation.