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Activation of the peroxisome proliferator-activated receptor γ counteracts sepsis-induced T cell cytotoxicity toward alloantigenic target cells

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Abstract

Sepsis still emerges as a major cause of patient death in intensive care units. Therefore, new therapeutic approaches are mandatory. Because during sepsis progression cytotoxic T lymphocytes (CTLs) can be activated in an autoimmune fashion contributing to multiorgan damage, it remains unclear whether CTLs are activated toward alloantigenic cells. This is important for patients receiving an immunosuppressive therapy to permit organ transplantation and, thus, known to be at high risk for developing sepsis. Therefore, we analyzed whether sepsis activates CTL toward alloantigenic target cells and whether this can be inhibited by PPARγ activation, known to block T helper cell responses. To mimic septic conditions, CTLs were isolated from cecal ligation and puncture-operated mice. CTL cytotoxicity was analyzed following a direct alloantigenic activation regime or following classical ex vivo splenocyte-driven activation in a cytotoxicity assay. With this readout, we found that CTL derived from septic mice enhanced cytotoxicity toward alloantigenic target cells, which was lowered by in vivo and ex vivo PPARγ activation. With CTL derived from T cell-specific PPARγ knockout mice, PPARγ activation was ineffective, pointing to a PPARγ-dependent mechanism. In vivo and ex vivo PPARγ activation reduced Fas and granzyme B expression in activated CTL.

Key message

  • In the sepsis CLP mouse model, CTLs are activated toward alloantigenic target cells.

  • Sepsis-mediated alloantigenic CTL activation is blocked in vivo by PPARγ activation.

  • PPARγ deletion or antagonization restored rosiglitazone-dependent inhibition of CTL cytotoxicity.

  • PPARγ inhibits the expression of Fas and granzyme B in CTLs.

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Acknowledgments

This research was supported by a grant from the Deutsche Forschungsgemeinschaft (KN493/11-1 and SFB 815 TP3). The work has been supported by the Else Kröner-Fresenius Foundation (EKFS), Research Training Group Translational Research Innovation—Pharma (TRIP), and the Landesoffensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz (LOEWE), Schwerpunkt: Anwendungsorientierte Arzneimittelforschung. We thank Nadja Wallner for the excellent technical assistance.

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The authors declare no conflict of interest related to this study.

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Authors and Affiliations

  1. Institute of Biochemistry I—Pathobiochemistry, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany

    Andreas von Knethen, Lisa Katharina Sha, Laura Kuchler, Annika Klara Giegerich, Martin Schulz & Bernhard Brüne

  2. Project Group Translational Medicine & Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    Tilo Knape

  3. Department of Nephrology, Medical Clinic III, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    Ingeborg A. Hauser

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  1. Andreas von Knethen
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Correspondence to Andreas von Knethen.

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von Knethen, A., Sha, L.K., Knape, T. et al. Activation of the peroxisome proliferator-activated receptor γ counteracts sepsis-induced T cell cytotoxicity toward alloantigenic target cells. J Mol Med 93, 633–644 (2015). https://doi.org/10.1007/s00109-014-1249-8

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  • DOI: https://doi.org/10.1007/s00109-014-1249-8

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