Environmental Cues Dictate the Fate of Individual CD8+ T Cells Responding to Infection

•Single polyclonal CD8 T cells generate distinct progenies based on infection type•Tissue-specific factors control single CD8 T cell fate within the same animal•Naive CD8 T cell precursor frequency does not predict clonal burst size•Overall CD8 T cell response is shaped by distinct contributions of effector subsets

SummaryMany 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.