Innate Immunity Protein Tag7 Induces 3 Distinct Populations of Cytotoxic Cells That Use Different Mechanisms to Exhibit Their Antitumor Activity on Human Leukocyte Antigen-Deficient Cancer Cells

Abstract

The search for new immune response mechanisms capable of controlling immune-evasive tumor cells devoid of the MHC antigen is a challenging task for immunologists. In this study, we found that the treatment of human peripheral blood lymphocytes with the innate immunity protein Tag7 (PGRP-S, PGLYRP1) induces differentiation of the populations of NK (natural killer) cells and CD8+ and CD4+ T lymphocytes that are cytotoxic for human leukocyte antigen-negative tumor cells. These populations employ different mechanisms of tumor cell lysis (based on the release of granzymes in the case of NK cells and on the FasL-Fas interaction in the case of CD8+ and CD4+ T lymphocytes) and induce different death pathways (apoptosis or necroptosis) in tumor cells. An analysis of genes activated in leukocyte populations after Tag7 treatment and experiments with specific inhibitors have shown that the TREM-1 receptor expressed on the monocyte cell surface is essential for activation of cytotoxic activity. Overall, the results of this study provide evidence for a novel role of the Tag7 protein in the immune response.

Tilorone activates NK cells and cytotoxic lymphocytes that kill HLA‐negative tumor cells

“…Analyzing the dependence of PBMC cytotoxicity on the time of incubation with tilorone, we revealed two peaks of cytotoxic activity (Fig. ), as in previous experiments with the PBMC fraction activated by Tag7 and IL‐2 . These results suggest that treatment with the above agents for different periods of time leads to activation of cytotoxic lymphocyte subpopulations that affect tumor cells in different ways.…”

“…Similar results were obtained in our previous experiments on PBMC treatment with Tag7 or IL-2:cytotoxic activity on day 4 was observed for NK cells and CD4+ lymphocytes; on day 6, NK cytotoxicity was lost, while that of CD4+ lymphocytes was retained, and CD8+ lymphocytes also acquired cytotoxic activity (11,12).…”

“…As follows from our previous data, different cytotoxic lymphocyte subpopulations activated by Tag7 or IL-2 induced different cell death mechanisms in target cells: NK cells killed HLA-negative tumor cells by secreting granzymes, whereas CD4+ and CD8+ lymphocytes killed them via the FasL-Fas interaction (11,12).…”

“…Human erythroblastoma K562 cells used in our experiments are HLA-negative but express on their surface at least two stress proteins: MICA (an unconventional MHC molecule) and Hsp70 (8,23). We have also shown that Tag7-or IL-2-activated cytotoxic T lymphocytes have surface receptors interacting with these stress molecules: CD8+ lymphocytes express the NK-activating receptor NKG-2D interacting with MICA, and CD4+ lymphocytes express the Tag7 protein that recognizes Hsp70 on K562 cells (8,12,23).…”

Assessment of in vitro bioactivities of Pis v 1 (2S albumin) and Pis v 2.0101 (11S globulin) proteins derived from pistachio (Pistacia vera L.)

“…Moreover, Tag7 complex with Hsp70 showed cytotoxic effects in many tumor cell lines. It seems that Tag7 can activate cytotoxic lymphocyte subpopulations [25]. Cytotoxicity of proteins may be exerted through different mechanisms including disruption of cell membrane integrity via depolarization, reducing the activity of membrane-bound enzymes, modification of the mevalonate pathway of metabolism and/or induction of apoptosis [35].…”