Human T regulatory cells can use the perforin pathway to cause autologous target cell death

Immunity. 2004 Oct;21(4):589-601. doi: 10.1016/j.immuni.2004.09.002.


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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • CD18 Antigens / immunology
  • CD18 Antigens / metabolism
  • CD4 Antigens / immunology
  • CD4 Antigens / metabolism
  • Cytotoxicity, Immunologic*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Fas Ligand Protein
  • Flow Cytometry
  • Granzymes
  • Humans
  • Lymphocyte Activation / immunology
  • Membrane Glycoproteins / immunology*
  • Membrane Glycoproteins / metabolism
  • Microscopy, Confocal
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • Receptors, Interleukin-2 / immunology
  • Receptors, Interleukin-2 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serine Endopeptidases / immunology
  • Serine Endopeptidases / metabolism
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology*
  • fas Receptor / immunology
  • fas Receptor / metabolism


  • CD18 Antigens
  • CD4 Antigens
  • FASLG protein, human
  • Fas Ligand Protein
  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Receptors, Interleukin-2
  • fas Receptor
  • Perforin
  • GZMB protein, human
  • Granzymes
  • Serine Endopeptidases
  • GZMA protein, human