Perforin and the granule exocytosis cytotoxicity pathway

Catálfamo, Marta; Henkart, Pierre A.

doi:10.1016/s0952-7915(03)00114-6

Cited by 141 publications

(116 citation statements)

References 52 publications

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“…Whatever the exact role of perforin, studies with knockout mice and with individuals suffering from genetic disorders in which perforin function has been abrogated have highlighted the crucial role this protein plays in lymphocyte-mediated cytotoxicity. 33,34 Firstly, the generation of perforin-deficient mice has demonstrated the absolute requirement of this protein for granzyme-dependent killing. [35][36][37] Perforin deficiency also results in an increased susceptibility to tumor formation and infection by a number of different pathogens.…”

Section: Perforin Facilitates Entry Of Granzymes Into the Target Cellmentioning

confidence: 99%

Mechanisms of granule-dependent killing

2007

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Section: Perforin Facilitates Entry Of Granzymes Into the Target Cellmentioning

confidence: 99%

Mechanisms of granule-dependent killing

2007

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“…In those cases, killing involves the formation of a mature immunological synapse between the effector cell and the target cell to ensure the transfer of various cytotoxic molecules from the effector to the target cells (37,38). This synapse forms a tight molecular environment, ensured by TCR-peptide-MHC (NK cells and its receptor) interaction, and by the engagement of adhesion molecules.…”

Section: Dnt Cell-mediated B Cell Death Requires Cell-to-cell Contactmentioning

confidence: 99%

Double-Negative T Cells, Activated by Xenoantigen, Lyse Autologous B and T Cells Using a Perforin/Granzyme-Dependent, Fas-Fas Ligand-Independent Pathway

Zhang

Wang

et al. 2006

The Journal of Immunology

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The ability to control the response of B cells is of particular interest in xenotransplantation as Ab-mediated hyperacute and acute xenograft rejection are major obstacles in achieving long-term graft survival. Regulatory T cells have been proven to play a very important role in the regulation of immune responses to self or non-self Ags. Previous studies have shown that TCRαβ+CD3+CD4−CD8− (double-negative (DN)) T cells possess an immune regulatory function, capable of controlling antidonor T cell responses in allo- and xenotransplantation through Fas-Fas ligand interaction. In this study, we investigated the possibility that xenoreactive DNT cells suppress B cells. We found that DNT cells generated from wild-type C57BL/6 mice expressed B220 and CD25 after rat Ag stimulation. These xenoreactive B220+CD25+ DNT cells lysed activated, but not naive, B and T cells. This killing, which took place through cell-cell contact, required participation of adhesion molecules. Our results indicate that Fas ligand, TGF-β, TNF-α, and TCR-MHC recognition was not involved in DNT cell-mediated syngenic cell killing, but instead this killing was mediated by perforin and granzymes. The xenoreactive DNT cells expressed high levels of granzymes in comparison to allo- or xenoreactive CD8+ T cells. Adoptive transfer of DNT cells in combination with early immune suppression by immunosuppressive analog of 15-deoxyspergualin, LF15-0195, significantly prolonged rat heart graft survival to 62.1 ± 13.9 days in mice recipients. In conclusion, this study suggests that xenoreactive DNT cells can control B and T cell responses in perforin/granzyme-dependent mechanisms. DNT cells may be valuable in controlling B and T cell responses in xenotransplantation.

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“…One of the granule proteins, perforin, is critical for entry of granule contents into the target cell, although the exact mechanism for this is unclear (reviewed in Ref. 22). Upon entry into the target cell, granule-associated serine proteases, in particular granzyme B, cause caspase activation and apoptosis in the target (reviewed in Ref.…”

Section: Signal 3 Tolerant Cd8 T Cells Degranulate In Response Tomentioning

confidence: 99%

Signal 3 Tolerant CD8 T Cells Degranulate in Response to Antigen but Lack Granzyme B to Mediate Cytolysis

Curtsinger

Lins

Johnson

et al. 2005

The Journal of Immunology

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Naive CD8 T cells that respond in vivo to Ag and costimulation in the absence of a third signal, such as IL-12, fail to develop cytolytic function and become tolerized. We show in this study that CD8 T cells purified from TCR transgenic mice and stimulated in vitro in the presence or absence of IL-12 form conjugates with specific target cells, increase intracellular Ca2+, and undergo degranulation to comparable extents. Perforin is also expressed at comparable levels in the absence or presence of a third signal, but expression of granzyme B depends upon IL-12. Levels of granzyme B also correlate strongly with the cytolytic activity of cells responding in vivo. In contrast, an increase in CD107a (lysosomal-associated membrane protein 1) expression resulting from degranulation cannot distinguish in vivo generated lytic effector cells from tolerized, noncytolytic cells. Thus, it appears that cells rendered tolerant as a result of stimulation in the absence of a third signal fail to lyse target cells because they are “shooting blanks.”

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Perforin and the granule exocytosis cytotoxicity pathway

Cited by 141 publications

References 52 publications

Mechanisms of granule-dependent killing

Mechanisms of granule-dependent killing

Double-Negative T Cells, Activated by Xenoantigen, Lyse Autologous B and T Cells Using a Perforin/Granzyme-Dependent, Fas-Fas Ligand-Independent Pathway

Signal 3 Tolerant CD8 T Cells Degranulate in Response to Antigen but Lack Granzyme B to Mediate Cytolysis

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