Regulation of Split Anergy in Natural Killer Cells by Inhibition of Cathepsins C and H and Cystatin F

Overview

Journal Oncotarget

Specialty Oncology

Date 2015 Aug 7

PMID 26247631

Citations 30

Authors

Spela Magister

Han-Ching Tseng

Vickie T Bui

Janko Kos

Anahid Jewett

Affiliations

Soon will be listed here.

Abstract

Freshly isolated human primary NK cells induce preferential lysis of Oral Squamous Carcinoma Stem Cells (OSCSCs) when compared to differentiated Oral Squamous Carcinoma Cells (OSCCs), while anti-CD16 antibody and monocytes induce functional split anergy in primary NK cells by decreasing the cytotoxic function of NK cells and increasing the release of IFN-γ. Since NK92 cells have relatively lower levels of cytotoxicity when compared to primary NK cells, and have the ability to increase secretion of regulatory cytokines IL-10 and IL-6, we used these cells as a model of NK cell anergy to identify and to study the upstream regulators of anergy. We demonstrate in this paper that the levels of truncated monomeric cystatin F, which is known to inhibit the functions of cathepsins C and H, is significantly elevated in NK92 cells and in anergized primary NK cells. Furthermore, cystatin F co-localizes with cathepsins C and H in the lysosomal/endosomal vesicles of NK cells. Accordingly, the mature forms of aminopeptidases cathepsins C and H, which regulate the activation of effector granzymes in NK cells, are significantly decreased, whereas the levels of pro-cathepsin C enzyme is increased in anergized NK cells after triggering of the CD16 receptor. In addition, the levels of granzyme B is significantly decreased in anti-CD16mAb and target cell anergized primary NK cells and NK92 cells. Our study provides the cellular and molecular mechanisms by which target cells may utilize to inhibit the cytotoxic function of NK cells.

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References

Magister S, Obermajer N, Mirkovic B, Svajger U, Renko M, Softic A . Regulation of cathepsins S and L by cystatin F during maturation of dendritic cells. Eur J Cell Biol. 2012; 91(5):391-401. DOI: 10.1016/j.ejcb.2012.01.001. View

Pietra G, Manzini C, Rivara S, Vitale M, Cantoni C, Petretto A . Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity. Cancer Res. 2012; 72(6):1407-15. DOI: 10.1158/0008-5472.CAN-11-2544. View

Rojnik M, Jevnikar Z, Doljak B, Turk S, Zidar N, Kos J . The influence of differential processing of procathepsin H on its aminopeptidase activity, secretion and subcellular localization in human cell lines. Eur J Cell Biol. 2012; 91(10):757-64. DOI: 10.1016/j.ejcb.2012.05.004. View

Maher K, Konjar S, Watts C, Turk B, Kopitar-Jerala N . Cystatin F regulates proteinase activity in IL-2-activated natural killer cells. Protein Pept Lett. 2014; 21(9):957-65. DOI: 10.2174/0929866521666140403124146. View

Rayet B, Gelinas C . Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 1999; 18(49):6938-47. DOI: 10.1038/sj.onc.1203221. View

Hashimoto S, Suzuki T, NAGAI S, Yamashita T, Toyoda N, Matsushima K . Identification of genes specifically expressed in human activated and mature dendritic cells through serial analysis of gene expression. Blood. 2000; 96(6):2206-14. View

Dahl S, Halkier T, Lauritzen C, Dolenc I, Pedersen J, Turk V . Human recombinant pro-dipeptidyl peptidase I (cathepsin C) can be activated by cathepsins L and S but not by autocatalytic processing. Biochemistry. 2001; 40(6):1671-8. DOI: 10.1021/bi001693z. View

Turk V, Turk B, Turk D . Lysosomal cysteine proteases: facts and opportunities. EMBO J. 2001; 20(17):4629-33. PMC: 125585. DOI: 10.1093/emboj/20.17.4629. View

Adkison A, Raptis S, Kelley D, Pham C . Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis. J Clin Invest. 2002; 109(3):363-71. PMC: 150852. DOI: 10.1172/JCI13462. View

10.

Turk B, Turk D, Salvesen G . Regulating cysteine protease activity: essential role of protease inhibitors as guardians and regulators. Curr Pharm Des. 2002; 8(18):1623-37. DOI: 10.2174/1381612023394124. View

11.

Obata-Onai A, Hashimoto S, Onai N, Kurachi M, Nagai S, Nagahata T . Comprehensive gene expression analysis of human NK cells and CD8(+) T lymphocytes. Int Immunol. 2002; 14(10):1085-98. DOI: 10.1093/intimm/dxf086. View

12.

Nathanson C, Wasselius J, Wallin H, Abrahamson M . Regulated expression and intracellular localization of cystatin F in human U937 cells. Eur J Biochem. 2002; 269(22):5502-11. DOI: 10.1046/j.1432-1033.2002.03252.x. View

13.

Jewett A, Wang M, Teruel A, Poupak Z, Bostanian Z, Park N . Cytokine dependent inverse regulation of CD54 (ICAM1) and major histocompatibility complex class I antigens by nuclear factor kappaB in HEp2 tumor cell line: effect on the function of natural killer cells. Hum Immunol. 2003; 64(5):505-20. DOI: 10.1016/s0198-8859(03)00039-9. View

14.

Honey K, Rudensky A . Lysosomal cysteine proteases regulate antigen presentation. Nat Rev Immunol. 2003; 3(6):472-82. DOI: 10.1038/nri1110. View

15.

Trapani J, Sutton V . Granzyme B: pro-apoptotic, antiviral and antitumor functions. Curr Opin Immunol. 2003; 15(5):533-43. DOI: 10.1016/s0952-7915(03)00107-9. View

16.

Vasiljeva O, Dolinar M, Turk V, Turk B . Recombinant human cathepsin H lacking the mini chain is an endopeptidase. Biochemistry. 2003; 42(46):13522-8. DOI: 10.1021/bi035355k. View

17.

Lee J, Lee K, Kim D, Heo D . Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol. 2004; 172(12):7335-40. DOI: 10.4049/jimmunol.172.12.7335. View

18.

Cappello F, Gatti E, Camossetto V, David A, Lelouard H, Pierre P . Cystatin F is secreted, but artificial modification of its C-terminus can induce its endocytic targeting. Exp Cell Res. 2004; 297(2):607-18. DOI: 10.1016/j.yexcr.2004.03.048. View

19.

Yannelli J, Sullivan J, Mandell G, Engelhard V . Reorientation and fusion of cytotoxic T lymphocyte granules after interaction with target cells as determined by high resolution cinemicrography. J Immunol. 1986; 136(2):377-82. View

20.

HEISKALA M, Ylikorkala O, Timonen T . Inhibition of human natural killer activity by monolayers of primary cell cultures. Nat Immun Cell Growth Regul. 1987; 6(1):1-11. View