Differential expression and biochemical activity of the immune receptor Tim-3 in healthy and malignant human myeloid cells

• Published in: Oncotarget Vol. 6; no. 32; pp. 33823 - 33833
• Main Authors: Gonçalves Silva, Isabel, Gibbs, Bernhard F, Bardelli, Marco, Varani, Luca, Sumbayev, Vadim V
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 20.10.2015
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Galectins - chemistry; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Hepatitis A Virus Cellular Receptor 2; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Interleukin-6 - metabolism; Leukemia, Myeloid, Acute - metabolism; Leukocytes - metabolism; Lipopolysaccharides - metabolism; Membrane Proteins - metabolism; Myeloid Cells - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; Protein Structure, Tertiary; Research Paper; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Stem Cell Factor - metabolism; TOR Serine-Threonine Kinases - metabolism; Tumor Necrosis Factor-alpha - metabolism; Up-Regulation; Vascular Endothelial Growth Factor A - metabolism; acute myeloid leukaemia; myeloid cells; Tim-3
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5257

The T cell immunoglobulin and mucin domain 3 (Tim-3) is a plasma membrane-associated receptor which is involved in a variety of biological responses in human immune cells. It is highly expressed in most acute myeloid leukaemia (AML) cells and therefore may serve as a possible target for AML therapy. However, its biochemical activities in primary human AML cells remain unclear. We therefore analysed the total expression and surface presence of the Tim-3 receptor in primary human AML blasts and healthy primary human leukocytes isolated from human blood. We found that Tim-3 expression was significantly higher in primary AML cells compared to primary healthy leukocytes. Tim-3 receptor molecules were distributed largely on the surface of primary AML cells, whereas in healthy leukocytes Tim-3 protein was mainly expressed intracellularly. In primary human AML blasts, both Tim-3 agonistic antibody and galectin-9 (a Tim-3 natural ligand) significantly upregulated mTOR pathway activity. This was in line with increased accumulation of hypoxia-inducible factor 1 alpha (HIF-1α) and secretion of VEGF and TNF-α. Similar results were obtained in primary human healthy leukocytes. Importantly, in both types of primary cells, Tim-3-mediated effects were compared with those induced by lipopolysaccharide (LPS) and stem cell factor (SCF). Tim-3 induced comparatively moderate responses in both AML cells and healthy leukocytes. However, Tim-3, like LPS, mediated the release of both TNF-α and VEGF, while SCF induced mostly VEGF secretion and did not upregulate TNF-α release.