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Cystatin F as a regulator of immune cell cytotoxicity

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Abstract

Cysteine cathepsins are lysosomal peptidases involved in the regulation of innate and adaptive immune responses. Among the diverse processes, regulation of granule-dependent cytotoxicity of cytotoxic T-lymphocytes (CTLs) and natural killer (NK) cells during cancer progression has recently gained significant attention. The function of cysteine cathepsins is regulated by endogenous cysteine protease inhibitors—cystatins. Whereas other cystatins are generally cytosolic or extracellular proteins, cystatin F is present in endosomes and lysosomes and is thus able to regulate the activity of its target directly. It is delivered to endosomal/lysosomal vesicles as an inactive, disulphide-linked dimer. Proteolytic cleavage of its N-terminal part leads to the monomer, the only form that is a potent inhibitor of cathepsins C, H and L, involved in the activation of granzymes and perforin. In NK cells and CTLs the levels of active cathepsin C and of granzyme B are dependent on the concentration of monomeric, active cystatin F. In tumour microenvironment, inactive dimeric cystatin F can be secreted from tumour cells or immune cells and further taken up by the cytotoxic cells. Subsequent monomerization and inhibition of cysteine cathepsins within the endosomal/lysosomal vesicles impairs granzyme and perforin activation, and provokes cell anergy. Further, the glycosylation pattern has been shown to be important in controlling secretion of cystatin F from target cells, as well as internalization by cytotoxic cells and trafficking to endosomal/lysosomal vesicles. Cystatin F is therefore an important mediator used by bystander cells to reduce NK and T-cell cytotoxicity.

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Abbreviations

C/EBP:

CCAAT/enhancer-binding protein

CCAAT box motif:

Cytosine–cytosine–adenosine–adenosine–thymidine box motif

CRES:

Cystatin-related epididymal spermatogenic protein

CTLs:

Cytotoxic T-lymphocytes

E64:

N-[N-(l-3-trans-Carboxyirane-2-carbonyl)-l-leucyl]-agmatine

LAMP-1:

Lysosomal-associated membrane protein 1

LPS:

Lipopolysaccharide

Mac-1:

Macrophage-1 antigen

MHC:

Major histocompatibility complex

NK cells:

Natural killer cells

poly I:C:

Polyinosinic:polycytidylic acid

RGD motif:

Arginyl-glycyl-aspartic acid motif

TLR:

Toll-like receptors

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Acknowledgements

We are grateful to Professor Roger H. Pain for critical reading of the manuscript.

Funding

This work was supported by the Grants P4-0127 and J4 6811 from the Research Agency of the Republic of Slovenia (to Janko Kos).

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Authors and Affiliations

  1. Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia

    Janko Kos, Milica Perišić Nanut, Mateja Prunk & Jerica Sabotič

  2. Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia

    Janko Kos

  3. Faculty of Pharmacy, University of Tuzla, Tuzla, Bosnia and Herzegovina

    Esmeralda Dautović

  4. The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, School of Dentistry, University of California-Los Angeles, Los Angeles, USA

    Anahid Jewett

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MP, MPN and ED drafted the manuscript. MPN and MP designed the figures. JK finalized the manuscript in consultation with JS and AJ.

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Correspondence to Janko Kos.

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Kos, J., Nanut, M.P., Prunk, M. et al. Cystatin F as a regulator of immune cell cytotoxicity. Cancer Immunol Immunother 67, 1931–1938 (2018). https://doi.org/10.1007/s00262-018-2165-5

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