NFATc1 controls the cytotoxicity of CD8+ T cells

Abstract

<jats:title>Abstract</jats:title><jats:p>Cytotoxic T lymphocytes are effector CD8<jats:sup>+</jats:sup> T cells that eradicate infected and malignant cells. Here we show that the transcription factor NFATc1 controls the cytotoxicity of mouse cytotoxic T lymphocytes. Activation of <jats:italic>Nfatc1</jats:italic><jats:sup> <jats:italic>−/−</jats:italic> </jats:sup> cytotoxic T lymphocytes showed a defective cytoskeleton organization and recruitment of cytosolic organelles to immunological synapses. These cells have reduced cytotoxicity against tumor cells, and mice with NFATc1-deficient T cells are defective in controlling Listeria infection. Transcriptome analysis shows diminished RNA levels of numerous genes in <jats:italic>Nfatc1</jats:italic><jats:sup> <jats:italic>−/−</jats:italic> </jats:sup> CD8<jats:sup>+</jats:sup> T cells, including <jats:italic>Tbx21</jats:italic>, <jats:italic>Gzmb</jats:italic> and genes encoding cytokines and chemokines, and genes controlling glycolysis. <jats:italic>Nfatc1</jats:italic><jats:sup> <jats:italic>−/−</jats:italic> </jats:sup>, but not <jats:italic>Nfatc2</jats:italic><jats:sup> <jats:italic>−/−</jats:italic> </jats:sup> CD8<jats:sup>+</jats:sup> T cells have an impaired metabolic switch to glycolysis, which can be restored by IL-2. Genome-wide ChIP-seq shows that NFATc1 binds many genes that control cytotoxic T lymphocyte activity. Together these data indicate that NFATc1 is an important regulator of cytotoxic T lymphocyte effector functions.</jats:p>