Journal article

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

  • Gonçalves Silva, Isabel School of Pharmacy, University of Kent, Anson Building, Kent, ME4 4TB, United Kingdom
  • Gibbs, Bernhard F. School of Pharmacy, University of Kent, Anson Building, Kent, ME4 4TB, United Kingdom
  • Bardelli, Marco Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Varani, Luca Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Sumbayev, Vadim V. School of Pharmacy, University of Kent, Anson Building, Kent, ME4 4TB, United Kingdom
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    16.09.2015
Published in:
  • Oncotarget. - 2015, vol. 6, no. 32, p. 33823-33833
English 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.
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  • English
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Medicine
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https://susi.usi.ch/usi/documents/319077
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