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.
Highlights
Natural killer (NK) cells are large granular lymphocytes that mediate natural immunity against variety of tumor and virally infected cells [1]
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
The interaction of NK cells with primary oral tumor cells was studied after treatment with IL-2 and/or anti CD16 antibody with and without monocytes
Summary
Natural killer (NK) cells are large granular lymphocytes that mediate natural immunity against variety of tumor and virally infected cells [1]. Cytotoxicity pathways appear to be dissociated from proliferation and secretion of cytokines in NK cells [4]. This response termedsplit anergyhas been observed in subsets of NK cells, NKDC (NK cells dissociated from tumor conjugates) and NKC (NK cells not dissociated from the tumor conjugate). Whereas NKDC responded to IL-2 activation and become cytotoxic, they were unresponsive to IL-2 mediated induction of proliferation or secretion of cytokines. NKC showed an inverse response namely, they did not display any cytotoxicity following IL-2 activation, but proliferated and secreted cytokines [4, 5]. IL-2 rescued anti-CD16 antibody mediated apoptosis induced in a subset of NK cells [8]
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