Abstract
Cytotoxic T lymphocytes and natural killer cells use the perforin/granzyme pathway to kill virally infected cells and tumor cells. Mutations in genes important for this pathway are associated with several human diseases. CD4(+) T regulatory (Treg) cells have emerged as important in the control of immunopathological processes. We have previously shown that human adaptive Treg cells preferentially express granzyme B and can kill allogeneic target cells in a perforin-dependent manner. Here, we demonstrate that activated human CD4(+)CD25(+) natural Treg cells express granzyme A but very little granzyme B. Furthermore, both Treg subtypes display perforin-dependent cytotoxicity against autologous target cells, including activated CD4(+) and CD8(+) T cells, CD14(+) monocytes, and both immature and mature dendritic cells. This cytotoxicity is dependent on CD18 adhesive interactions but is independent of Fas/FasL. Our findings suggest that the perforin/granzyme pathway is one of the mechanisms that Treg cells can use to control immune responses.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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CD18 Antigens / immunology
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CD18 Antigens / metabolism
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CD4 Antigens / immunology
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CD4 Antigens / metabolism
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Cytotoxicity, Immunologic*
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Fas Ligand Protein
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Flow Cytometry
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Granzymes
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Humans
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Lymphocyte Activation / immunology
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Membrane Glycoproteins / immunology*
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Membrane Glycoproteins / metabolism
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Microscopy, Confocal
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Perforin
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Pore Forming Cytotoxic Proteins
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Receptors, Interleukin-2 / immunology
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Receptors, Interleukin-2 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Serine Endopeptidases / immunology
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Serine Endopeptidases / metabolism
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Signal Transduction / immunology*
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T-Lymphocytes / immunology*
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fas Receptor / immunology
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fas Receptor / metabolism
Substances
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CD18 Antigens
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CD4 Antigens
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FASLG protein, human
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Fas Ligand Protein
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Membrane Glycoproteins
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Pore Forming Cytotoxic Proteins
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Receptors, Interleukin-2
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fas Receptor
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Perforin
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GZMB protein, human
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Granzymes
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Serine Endopeptidases
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GZMA protein, human