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

Milica Periå¡Iä‡ Nanut,Janko Kos,Jerica Sabotiä,Anahid Jewett

doi:10.3389/fimmu.2014.00616

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.

Highlights

Peptidases are enzymes that catalyze the hydrolysis of peptide bonds in a polypeptide chain
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 proteolytic activity of peptidases is controlled by a variety of mechanisms: [1] regulation of their expression at transcriptional and/or translational levels; [2] synthesis of peptidases as inactive zymogens; [3] activation of peptidases by co-factors; [4] recognition and cleavage of a particular peptide bond flanked by specific amino acids; [5] compartmentalization in granules or endolysosomal vesicles separating them from their substrates; and [6] binding of peptidase inhibitors to the active site preventing access to substrates [2]

Summary

Introduction

Peptidases are enzymes that catalyze the hydrolysis of peptide bonds in a polypeptide chain. Cysteine cathepsins are lysosomal peptidases involved at different levels in the processes of the innate and adaptive immune responses.

Results

Conclusion