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

作者：von Knethen Andreas^*; Sha Lisa Katharina; Knape Tilo; Kuchler Laura; Giegerich Annika Klara; Schulz Martin; Hauser Ingeborg A; Bruene Bernhard

来源：Journal of Molecular Medicine-JMM, 2015, 93(6): 633-644.

DOI：10.1007/s00109-014-1249-8

• Alloantigenic
• CD8(+) T cell
• Cytotoxicity
• PPAR gamma
• Sepsis

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 PPAR gamma 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 PPAR gamma activation. With CTL derived from T cell-specific PPAR gamma knockout mice, PPAR gamma activation was ineffective, pointing to a PPAR gamma-dependent mechanism. In vivo and ex vivo PPAR gamma activation reduced Fas and granzyme B expression in activated CTL.

• 出版日期2015-6