Fratricide of CD8+ cytotoxic T lymphocytes is dependent on cellular activation and perforin-mediated killing.
CD8+ CTL mediate the destruction of cells displaying foreign peptides in association with class I MHC molecules. Since CD8+ CTL themselves express class I MHC molecules, a phenomenon known as "fratricide" can be elicited by T cells presenting antigens to other CTL. To gain insight into this mechanism, fratricide was induced in a clone of class I-restricted CD8+ CTL by incubating the T cells with their agonist ligand, an octamer peptide derived from chicken ovalbumin. Our results indicate that agonist peptide not only stimulates proliferation and cytolysis of CTL but also initiates signaling pathways that are pertinent to T cell activation, including the mobilization of transcription factors. Also consistent with T cell activation, fratricide induced the transcription and translation of the pro-inflammatory cytokines TNF-alpha and IFN-gamma. Finally, the essential role of perforin, as opposed to Fas/FasL, in fratricide was demonstrated by the selective inhibition of cytolysis with an inhibitor of the perforin pathway, the absence of FasL expression on T cells and the presence of lytic granules visible by electron microscopy. Collectively, these findings reveal that fratricide is mediated by T cell activation and perforin-mediated cytolysis. These results may have implications for the regulation of CD8+ CTL in immune responses.
Dana-Farber Cancer Institute, Department of Pediatric Oncology, Harvard Medical School, Boston, USA.
Michael Wei-Chih
MW
Su
Saiju
S
Pyarajan
Jin-Hong
JH
Chang
Chao-Lan
CL
Yu
Yong-Jiu
YJ
Jin
York-Dieter
YD
Stierhof
Peter
P
Walden
Steven J
SJ
Burakoff
D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000502:physiology; D004789:Enzyme Activation; D005089:Exocytosis; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D054353:Perforin; D010766:Phosphorylation; D052899:Pore Forming Cytotoxic Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014157:Transcription Factors / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D052899:Pore Forming Cytotoxic Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases