NFATc1 controls the cytotoxicity of CD8+ T cells

Stefan Klein-Hessling; Khalid Muhammad; Matthias Klein; Tobias Pusch; Ronald Rudolf; Jessica Flöter; Musga Qureischi; Andreas Beilhack; Martin Vaeth; Carsten Kummerow; Christian Backes; Rouven Schoppmeyer; Ulrike Hahn; Markus Hoth; Tobias Bopp; Friederike Berberich-Siebelt; Amiya Patra; Andris Avots; Nora Müller; Almut Schulze; Edgar Serfling

doi:10.1038/s41467-017-00612-6

NFATc1 controls the cytotoxicity of CD8⁺ T cells

Stefan Klein-Hessling, Khalid Muhammad, Matthias Klein, Tobias Pusch, Ronald Rudolf, Jessica Flöter, Musga Qureischi, Andreas Beilhack, Martin Vaeth, Carsten Kummerow, Christian Backes, Rouven Schoppmeyer, Ulrike Hahn, Markus Hoth, Tobias Bopp, Friederike Berberich-Siebelt, Amiya Patra, Andris Avots, Nora Müller, Almut SchulzeEdgar Serfling

Research output: Contribution to journal › Article › peer-review

139 Citations (Scopus)

Abstract

Cytotoxic T lymphocytes are effector CD8⁺ 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 Nfatc1 ^-/- 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 Nfatc1 ^-/- CD8⁺ T cells, including Tbx21, Gzmb and genes encoding cytokines and chemokines, and genes controlling glycolysis. Nfatc1 ^-/-, but not Nfatc2 ^-/- CD8⁺ 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.

Original language	English
Article number	511
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00612-6
Publication status	Published - Dec 1 2017
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-017-00612-6

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Klein-Hessling, S., Muhammad, K., Klein, M., Pusch, T., Rudolf, R., Flöter, J., Qureischi, M., Beilhack, A., Vaeth, M., Kummerow, C., Backes, C., Schoppmeyer, R., Hahn, U., Hoth, M., Bopp, T., Berberich-Siebelt, F., Patra, A., Avots, A., Müller, N., ... Serfling, E. (2017). NFATc1 controls the cytotoxicity of CD8⁺ T cells. Nature Communications, 8(1), Article 511. https://doi.org/10.1038/s41467-017-00612-6

Klein-Hessling, S, Muhammad, K, Klein, M, Pusch, T, Rudolf, R, Flöter, J, Qureischi, M, Beilhack, A, Vaeth, M, Kummerow, C, Backes, C, Schoppmeyer, R, Hahn, U, Hoth, M, Bopp, T, Berberich-Siebelt, F, Patra, A, Avots, A, Müller, N, Schulze, A & Serfling, E 2017, 'NFATc1 controls the cytotoxicity of CD8⁺ T cells', Nature Communications, vol. 8, no. 1, 511. https://doi.org/10.1038/s41467-017-00612-6

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abstract = "Cytotoxic T lymphocytes are effector CD8+ 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 Nfatc1 -/- 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 Nfatc1 -/- CD8+ T cells, including Tbx21, Gzmb and genes encoding cytokines and chemokines, and genes controlling glycolysis. Nfatc1 -/-, but not Nfatc2 -/- CD8+ 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.",

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AU - Qureischi, Musga

AU - Beilhack, Andreas

AU - Vaeth, Martin

AU - Kummerow, Carsten

AU - Backes, Christian

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AU - Hahn, Ulrike

AU - Hoth, Markus

AU - Bopp, Tobias

AU - Berberich-Siebelt, Friederike

AU - Patra, Amiya

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AU - Müller, Nora

AU - Schulze, Almut

AU - Serfling, Edgar

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N2 - Cytotoxic T lymphocytes are effector CD8+ 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 Nfatc1 -/- 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 Nfatc1 -/- CD8+ T cells, including Tbx21, Gzmb and genes encoding cytokines and chemokines, and genes controlling glycolysis. Nfatc1 -/-, but not Nfatc2 -/- CD8+ 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.

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NFATc1 controls the cytotoxicity of CD8⁺ T cells

Abstract

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