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

By W. Grossman, J. Verbsky, W. Barchet, M. Colonna, J. Atkinson, T. Ley. Immunity, 2004

1,109 citations recorded by the source corpus.

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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/e9e082bc4e6dd678090bba58bf18c1e2cbac209e

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Citations in the corpus

CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation–mediated apoptosis of effector CD4+ T cells (2007, background): “Hence, T reg cell–induced apoptosis was not due to cytolysis of responder T cells or to the triggering of any other known active apoptosis mechanis”
Cutting Edge: Contact-Mediated Suppression by CD4+CD25+ Regulatory Cells Involves a Granzyme B-Dependent, Perforin-Independent Mechanism1 (2005, background): “Moreover, Ley and coworkers (16) have shown CD4 CD25 Treg in the human system mediate suppression with requirement for granzyme A (GZ-A).”
Regulatory T Cells: Mechanisms of Differentiation and Function (2012, background): “Cytolysis of target cells as a means for Treg cell–mediated suppression was first suggested by the finding that, in human Treg cells, granzyme A can be induced by a combination of CD3 and CD46 stimulation, resulting in the induction of apoptosis in activated target cells (223).”
A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3 (2005, background): “In addition, after activation, human T reg cells may directly kill activated CD4 and CD8 T cells in a perforin- or granzyme-dependent wa”
Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. (2007, methodology): “Immunity 27, 635–646, October 2007 ª2007 Elsevier Inc. 643 perforin-granzyme pathway to kill target cells as a mecha- nism of suppression (Grossman et al., 2004a; Zhao et al., 2006).”
Molecular Mechanisms of Treg-Mediated T Cell Suppression (2012, background): “It was shown that upon CD3/CD46 activation, human nTregs express the serine protease granzyme (Gzm) A and kill CD4+ T cells and other target cells in a perforin-dependent manner, yet independent of the death receptor CD95 (Grossman et al., 2004).”
Regulatory T cells, tumour immunity and immunotherapy (2006, background): “Activated human T Reg cells express granzyme A and kill T cells and APCs through perfori”
Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice (2007, result): “Reports have suggested that T reg cells kill immature myeloid DC in a granzyme-dependent way in vitro ; however, we failed to find evidence to support that idea, as neither DC apoptosis nor survival was altered after T reg cell ablatio”
Tumor‐induced tolerance and immune suppression by myeloid derived suppressor cells (2008, background): “Treg-dependent suppression is cell contact mediated by cell-bound TGF-b and CTLA-4/CD80 and CD86 interaction, mostly acting on the transcriptional control of IL-2 in T-effector cells (137) or promoting IDO expression in myeloid DCs (138–140), respectively.”
The Foxp3+ regulatory T cell: a jack of all trades, master of regulation (2008, result): “Other studies have shown that T reg cells can kill T eff cells directly in culture through the release of granzyme B and perfori”
Mechanisms of foxp3+ T regulatory cell-mediated suppression. (2009, background): “Human CD4+CD25+Foxp3+ Treg cells can be activated by a combination of antibodies to CD3 and CD46 to express granzyme A and kill activated CD4+ and CD8+ T cells and other cell types in a perforin-dependent, Fas-FasL-independent manner (Grossman et al., 2004).”
Mechanisms of suppression by suppressor T cells (2005, background): “Human CD4 + CD25 + Foxp3-expressing T cells can be activated by a combination of antibodies to CD3 and CD46 to express granzyme A and kill activated CD4 + and CD8 + T cells by a perforin-dependent mechanism in a reaction that does not involve Fas–Fas ligand bindin”
A function for interleukin 2 in Foxp3-expressing regulatory T cells (2005, background): “The last two have been linked to the direct killing of responder T cells by preactivated Foxp3 + T reg cell”