Cysteine cathepsins as regulators of the cytotoxicity of NK and T cells

Abstract

Cysteine cathepsins are lysosomal peptidases involved at different levels in the processes of the innate and adaptive immune responses. Some, such as cathepsins B, L, and H are expressed constitutively in most immune cells. In cells of innate immunity they play a role in cell adhesion and phagocytosis. Other cysteine cathepsins are expressed more specifically. Cathepsin X promotes dendritic cell maturation, adhesion of macrophages, and migration of T cells. Cathepsin S is implicated in major histocompatibility complex class II antigen presentation, whereas cathepsin C, expressed in cytotoxic T lymphocytes and natural killer (NK) cells, is involved in processing pro-granzymes into proteolytically active forms, which trigger cell death in their target cells. The activity of cysteine cathepsins is controlled by endogenous cystatins, cysteine protease inhibitors. Of these, cystatin F is the only cystatin that is localized in endosomal/lysosomal vesicles. After proteolytic removal of its N-terminal peptide, cystatin F becomes a potent inhibitor of cathepsin C with the potential to regulate pro-granzyme processing and cell cytotoxicity. This review is focused on the role of cysteine cathepsins and their inhibitors in the molecular mechanisms leading to the cytotoxic activity of T lymphocytes and NK cells in order to address new possibilities for regulation of their function in pathological processes.

Keywords: cathepsins; cystatins; cytotoxic T cells; cytotoxicity; natural killer cells.

Figure 1

Colocalization of cathepsin X and adaptor protein talin-1 in T cells (120). Primary CD4⁺ T cells, Jurkat cells, and cathepsin X-overexpressing Jurkat cells were allowed to migrate on ICAM-1- precoated slides for 30 min, and analyzed for colocalization of talin and cathepsin X. Specific antibodies for talin-1 (red) and cathepsin X (2F12, green) have been applied. The threshold level for this display corresponds to one-third of the maximal brightness level. Colocalization is represented by the pixels above the threshold in both channels on the contour plot and on the merged image (white color). Original scale bar, 5 μm.

Figure 2

Schematic representation of the regulation of NK cell/CD8⁺ T cell cytotoxicity by cathepsins. On target cell recognition, cytotoxic cells secrete the content of their cytotoxic granules into the immunological synapse, leading to the caspase-dependent or independent cell death of target cells. The major cytotoxic mediators are activated by limited proteolysis by cathepsins C and H (granzyme A and B) and, possibly, cathepsin L (perforin). N-terminally processed cystatin F is a potent inhibitor of cathepsins C, H, and L and thus a potential regulator of NK cell/CD8⁺ T cell cytotoxicity. Exocytosed cysteine cathepsins may also be involved in inhibition of perforin, contributing to self-protection of cytotoxic cells from the contents of their cytotoxic granules.