Cytotoxic T lymphocytes require transcription for infiltration but not target cell lysis

Abstract

Effector cytotoxic T lymphocytes (CTLs) are critical for ridding the body of infected or cancerous cells. CTL T cell receptor (TCR) ligation not only drives the delivery and release of cytolytic granules but also initiates a new wave of transcription. In order to address whether TCR‐induced transcriptomic changes impact the ability of CTLs to kill, we asked which genes are expressed immediately after CTLs encounter targets and how CTL responses change when inhibiting transcription. Our data demonstrate that while expression of cytokines/chemokines and transcriptional machinery depend on transcription, cytotoxic protein expression and cytolytic activity are relatively robust to transcription blockade, with CTLs lysing nearby target cells for several hours after actinomycin D treatment. Monitoring CTL movement among target cells after inhibiting transcription demonstrates an infiltration defect that is not rectified by provision of exogenous cytokine/chemokine gradients, indicating a cell‐intrinsic transcriptional requirement for infiltration. Together, our results reveal differential molecular control of CTL functions, separating recruitment and infiltration from cytolysis. image Cytotoxic T lymphocytes initiate de novo transcription immediately after target encounter. While already primed for cytolysis, these transcriptomic changes enable cytokine/chemokine expression and infiltration between target cells, revealing differential molecular controls for cytolysis and recruitment. Target cell recognition triggers rapid transcriptomic changes in CTLs. Messenger RNAs for cytokines/chemokines but not for cytolytic proteins are upregulated. Inhibition of de novo transcription blocks CTL infiltration and this cannot be rectified by exogenous cytokines/chemokines. While CTLs are pre‐armed for cytolysis, they require de novo transcription to migrate between targets.