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

: Knethen, A. von; Sha, L.K.; Knape, T.; Kuchler, L.; Giegerich, A.K.; Schulz, M.; Hauser, I.A.; Brüne, B.


Journal of molecular medicine 93 (2015), Nr.6, S.633-644
ISSN: 0946-2716
ISSN: 1432-1440
Fraunhofer IME ()

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 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 f ound that CTL derived from septic mice enhanced cytotoxicity toward alloantigenic target cells, which was lowered by in vivo and ex vivo PPAR activation. With CTL derived from T cell-specific PPAR knockout mice, PPAR activation was ineffective, pointing to a PPAR-dependent mechanism. In vivo and ex vivo PPAR 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 PPAR activation.PPAR deletion or antagonization restored rosiglitazone-dependent inhibition of CTL cytotoxicity.PPAR inhibits the expression of Fas and granzyme B in CTLs.