Human T regulatory cells can use the perforin pathway to cause autologous target cell death.
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.
Department of Pediatrics, Division of Hematology/Oncology, St. Louis Children's Hospital, St. Louis, MO 63110, USA.
William J
WJ
Grossman
James W
JW
Verbsky
Winfried
W
Barchet
Marco
M
Colonna
John P
JP
Atkinson
Timothy J
TJ
Ley
D018821:CD18 Antigens / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D053804:Granzymes; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D018613:Microscopy, Confocal; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D015375:Receptors, Interleukin-2 / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism
D018821:CD18 Antigens; D015704:CD4 Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D015375:Receptors, Interleukin-2; D019014:fas Receptor; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human