Cytokines TNFα, IFNγ and IL-2 Are Responsible for Signal Transmission from the Innate Immunity Protein Tag7 (PGLYRP1) to Cytotoxic Effector Lymphocytes

Abstract

Studies on the mechanisms of activation of cytotoxic lymphocyte subpopulations are an important research direction in modern immunology. This study provides a detailed analysis of the effect of Tag7 (PGRP-S, PGLYRP1) on the development of lymphocyte subpopulations cytotoxic against MHC-negative tumor cells in a pool of peripheral blood mononuclear cells (PBMCs). The results show that Tag7 can bind to the TREM-1 receptor on the surfaces of monocytes, thereby triggering the expression of mRNA TNFα and IFNγ. The appearance of these cytokines in conditioned medium leads to IL-2 cytokine secretion by CD3+CD4+ lymphocytes. In turn, IL-2 facilitates unspecific activation of three cytotoxic cell subpopulations in the PBMC pool: NK (CD16+CD56+), CD3+CD4+ and CD3+CD8+. These subpopulations appear after a certain period of incubation with Tag7 and show toxicity against tumor cells.

Hsp70 Interacts with the TREM-1 Receptor Expressed on Monocytes and Thereby Stimulates Generation of Cytotoxic Lymphocytes Active against MHC-Negative Tumor Cells

“…On the other hand, with an increase in the ratio of mc (-) PBMCs to the target cells, the cytotoxic activity also raises (Supplement 4). As was shown in our recent study [17], monocytes and CD4+ T-lymphocytes are also involved in the activation of cytotoxic lymphocytes upon the interaction of TREM-1 with the innate immunity protein Tag7, with monocytes secreting cytokines TNFα and IFNγ, while CD4+ T-lymphocytes showing activation of IL-2 gene expression followed by IL-2 secretion. Therefore, we tested how the expression of genes encoding these cytokines and their secretion change upon treatment with Hsp70.…”

“…We have shown previously that the innate immunity protein Tag7 (PGLYRP1), recently described as a ligand for TREM-1, also induces activation of cytotoxic lymphocytes that kill MHC-negative tumor cells [16]. The interaction of Tag7 with TREM-1 in monocytes stimulates the expression of genes for TNFα and IFNγ and secretion of these cytokines followed by activation of CD4+T-Lymphocytes, which leads to the enhanced expression of IL-2 gene and secretion of this cytokine, which plays a key role in the activation of cytotoxicity [17].…”

“…The PBMC pool was treated with Hsp70 for six days, and activated lymphocytes were tested for cytotoxic activity by incubating them with target cells for 3 to 24 h. As follows from Figure 2А, Hsp70-activated lymphocytes showed cytotoxic activity against target cells at different time intervals, which could be explained by induction of different mechanisms of cytotoxicity at the corresponding intervals. Previously, it was shown that Tag7 binds to TREM-1 and induces appearance of cytotoxic lymphocytes [17]. Due to this fact, Tag7-activated lymphocytes were used as positive control.…”

N-Terminal Peptide of PGLYRP1/Tag7 Is a Novel Ligand for TREM-1 Receptor

“…This stage is crucial in the elimination of tumor cells through FasL-Fas interaction by CD4 lymphocytes. It has been shown that incubation of Tag7 with PBMCs from healthy donors stimulates expression and release of pro-inflammatory cytokines, and also induces the appearance of cytotoxic lymphocytes that are able to eliminate HLA-negative tumor cells [ 32 , 33 ].…”

Protein PGLYRP1/Tag7 Peptides Decrease the Proinflammatory Response in Human Blood Cells and Mouse Model of Diffuse Alveolar Damage of Lung through Blockage of the TREM-1 and TNFR1 Receptors

“…TREM-1 is important as an amplifier of the inflammatory response. The described ligands of TREM-1 include the high mobility group box 1 protein (HMGBI) nuclear protein and the innate immune protein PGLYRP1 (Tag7) [7][8][9]. Our recent study has demonstrated that Hsp70, the major heat shock protein, can be also considered as another ligand for TREM-1 [10].…”