Functional dissection of the granzyme family: cell death and inflammation

Abstract

Cytotoxic lymphocytes rapidly respond and destroy both malignant cells and cells infected with intracellular pathogens. One mechanism, known as granule exocytosis, employs the secretory granules of these lymphocytes. These include the pore-forming protein perforin (pfp) and a family of serine proteases known as granzymes that cleave and activate effector molecules within the target cell. Over the past two decades, the study of granzymes has largely focused on the ability of these serine proteases to induce cell death. More recently, sophisticated mouse models of disease coupled with gene-targeted mice have allowed investigators to ask why granzyme subfamilies are encoded on different chromosomal loci and what broader role these enzymes might play in inflammation and immune response. Here, we provide a brief overview of the granzyme superfamily, their relationship to pfp, and their reported functions in apoptosis. This overview is followed by a comprehensive analysis of the less characterized and developing field regarding the non-apoptotic functions of granzymes.

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

“…In addition, it has been shown recently that cord blood contains a small proportion of Th1, Th2, and Th17 effector memory-like CD4 + αβ T cells, indicating the functional plasticity of this subset (74). We also showed that fetal blood Vγ9Vδ2 T cells express a particular pattern of granzymes with high coexpression of granzymes A and K but no expression of the classical killer granzyme B (75,76). Perforin was enriched in Vγ9Vδ2 T cells at the RNA level but not at the protein level, in contrast to adult Vγ9Vδ2 T cells, which are known to express perforin, granzyme B, and granulysin protein (3).…”

“…Alternatively, the fetal Vγ9Vδ2 T-cell wave might be needed to prepare the fetus for its interaction with phosphoantigen-producing commensal bacteria after birth (13,83) or could contribute to the formation of tissues or organs during fetal development, for example via the highly expressed granzymes A and K, which have been shown to degrade extracellular matrix proteins (75). The semi-invariant Vγ9Vδ2 TCR could serve as a target for novel vaccination strategies in early life, for which there is a clear medical need, either in utero or after birth (84,85).…”

Cystatins, cysteine peptidase inhibitors, as regulators of immune cell cytotoxicity

“…In humans five different granzymes have been described, granzymes A, B, H, M and K, with different substrate specificities and expression (91,92). Similarly to other serine peptidases, granzymes are activated by a two-step process.…”

“…The expression of granzymes is in generally limited to lymphoid cells and the only cells known to synthesize and store granzymes constitutively are NK cells, natural killer T cells (NKT), and gd T cells, whereas in other cells granzymes are expressed only after stimulation, e.g. antigen stimulation in CTLs (92). In addition, non-cytotoxic roles for granzymes have been proposed, such as direct cleavage of viral proteins or activation of pro-inflammatory cytokines (83).…”

Testosterone regulates granzyme K expression in rat testes

“…Th ey are secretory granule proteases, generally residing inside cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells that help in the elimination of the cancerous and virus infected cells by cleaving specifi c intracellular substrates (Chowdhury and Lieberman 2008;Chavez-Galan et al 2009). Although granzymes located inside CTLs and NK cells are generally cytolytic, many granzyme variants in non-immune cells (granulosa cells, chondrocytes and Sertoli cells) have non-apoptotic extracellular functions such as remodeling of the extracellular matrix, inducing infl ammation and signal transduction (Amsterdam et al 2003;Buzza and Bird 2006;Chowdhury and Lieberman 2008;Romero and Andrade 2008;Anthony et al 2010). In human and mouse testes, GZMB is expressed in the Sertoli cells and germ cells, and Gzmn is expressed only in the germ cells (Hirst et al 2001;Takano et al 2004).…”