Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance.

By Xuefang Cao, Sheng F. Cai, T. Fehniger, Jiling Song, Lynne I Collins, D. Piwnica-Worms, T. Ley. Immunity, 2007

1,003 citations recorded by the source corpus.

Granzyme B is important for the ability of NK cells and CD8(+) T cells to kill their targets. However, we showed here that granzyme B-deficient mice clear both allogeneic and syngeneic tumor cell lines more efficiently than do wild-type (WT) mice. To determine whether regulatory T (Treg) cells utilize granzyme B to suppress immune responses against these tumors, we examined the expression and function of granzyme B in Treg cells. Granzyme B was not expressed in naive Treg cells but was highly expressed in 5%-30% of CD4(+)Foxp3(+) Treg cells in the tumor environment. Adoptive transfer of WT Treg cells, but not granzyme B- or perforin-deficient Treg cells, into granzyme B-deficient mice partially restored susceptibility to tumor growth; Treg cells derived from the tumor environment could induce NK and CD8(+) T cell death in a granzyme B- and perforin-dependent fashion. Granzyme B and perforin are therefore relevant for Treg cell-mediated suppression of tumor clearance in vivo.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/bacbe2cf32bd51746cc1c0abf04afb0c0fbe8a6a

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Citations in the corpus

Mechanisms of foxp3+ T regulatory cell-mediated suppression. (2009, background): “It has been difficult to demonstrate granzyme B expression by Treg cells in vivo, but Cao et al. (2007) demonstrate that 5%–30% of Treg cells in a tumor microenvironment express granzyme B and these Treg CTLA-4 on the surface of Treg cells downregulates or prevents the upregulation of CD80 and…”
Molecular Mechanisms of Treg-Mediated T Cell Suppression (2012, background): “, 2008), but it might counteract tumor clearance by killing tumor-reactive NK cells and CD8+ T cells (Cao et al., 2007).”
T Regulatory Cells: Key Players in Tumor Immune Escape and Angiogenesis (2012, background): “Of importance, Cao and colleagues (27) were able to show that”
Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation (2008, background): “In addition to this two-step cell contactdependent suppression, Tregs might further differentiate in vivo as the third step to exert other suppressive activities, such as secretion of IL-10 in a particular local milieu and granzyme-B-dependent cytotoxicity (1, 28, 37, 38).”
How regulatory T cells work (2008, background): “More recently, T Reg cells were shown to suppress the ability of NK cells and CTLs to clear tumours by killing these cells in a granzyme-B-dependent and perforin-dependent manne”
The PD-1 Pathway in Tolerance and Autoimmunity (2010, background): “Granzyme B was not detected in naive Tregs, but was expressed in CD4Foxp3 Tregs from tumor-challenged mice (122).”
Regulatory T Cells: Mechanisms of Differentiation and Function (2012, result): “These findings have been further confirmed by the in vivo studies in which granzyme B has been critical in maintaining Treg cell–dependent long-lived skin graft tolerance as well as in Treg cell–mediated suppression of tumor clearance (226, 227).”
Regulatory T cells exert checks and balances on self tolerance and autoimmunity (2010, background): “Perforin- or granzyme-expressing Foxp3 + T reg cells are also rare in the spleen but are abundant in a tumor environmen”