title: Cardiomyocytes display low mitochondrial priming and are highly resistant toward cytotoxic T-cell killing.
abstract: Following heart transplantation, alloimmune responses can cause graft rejection by damaging donor vascular and parenchymal cells. However, it remains unclear whether cardiomyocytes are also directly killed by immune cells. Here, we used two-photon microscopy to investigate how graft-specific effector CD8(+) T cells interact with cardiomyocytes in a mouse heart transplantation model. Surprisingly, we observed that CD8(+) T cells are completely impaired in killing cardiomyocytes. Even after virus-mediated preactivation, antigen-specific CD8(+) T cells largely fail to lyse these cells although both cell types engage in dynamic interactions. Furthermore, we established a two-photon microscopy-based assay using intact myocardium to determine the susceptibility of cardiomyocytes to undergo apoptosis. This feature, also known as mitochondrial priming reveals an unexpected weak predisposition of cardiomyocytes to undergo apoptosis in situ. These observations together with the early exhaustion phenotype of graft-infiltrating specific T cells provide an explanation why cardiomyocytes are largely protected from direct CD8(+) T-cell-mediated killing.
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Halle
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Pooja
authors.initials: P
authors.lastname: Mishra
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherr
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pietzsch
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Willenzon
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Janssen
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Boelter
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eder
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Förster
keywords: Cardiomyocytes; Cytotoxic T cells; Mitochondrial priming; T-cell exhaustion; Two-photon microscopy