title: Activation of the peroxisome proliferator-activated receptor γ counteracts sepsis-induced T cell cytotoxicity toward alloantigenic target cells.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Biochemistry I-Pathobiochemistry, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany, vonknethen@biochem.uni-frankfurt.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Knethen
authors.forename: Lisa Katharina
authors.initials: LK
authors.lastname: Sha
authors.forename: Tilo
authors.initials: T
authors.lastname: Knape
authors.forename: Laura
authors.initials: L
authors.lastname: Kuchler
authors.forename: Annika Klara
authors.initials: AK
authors.lastname: Giegerich
authors.forename: Martin
authors.initials: M
authors.lastname: Schulz
authors.forename: Ingeborg A
authors.initials: IA
authors.lastname: Hauser
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
mesh_terms: D000818:Animals; D003602:Cytotoxicity, Immunologic; D005786:Gene Expression Regulation; D053804:Granzymes / Q000235:genetics; D006801:Humans; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000276:immunology*; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019014:fas Receptor / Q000235:genetics
chemical_list: D007519:Isoantigens; D047495:PPAR gamma; D019014:fas Receptor; D053804:Granzymes