Gonçalves Silva, Isabel Gibbs, Bernhard F. Bardelli, Marco Varani, Luca Sumbayev, Vadim V. 2015-09-16 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. application/pdf https://n2t.net/ark:/12658/srd1319077 https://susi.usi.ch/global/documents/319077 https://susi.usi.ch/documents/319077/files/Goncalves_Silva_O_2015.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.18632/oncotarget.5257 info:eu-repo/semantics/altIdentifier/ark/12658/srd1319077 info:eu-repo/semantics/openAccess CC BY Oncotarget. - 2015, vol. 6, no. 32, p. 33823-33833 Tim-3 Acute myeloid leukaemia Myeloid cells info:eu-repo/classification/udc/61 Differential expression and biochemical activity of the immune receptor Tim-3 in healthy and malignant human myeloid cells http://purl.org/coar/resource_type/c_6501