title: Antigen-independent induction of Tim-3 expression on human T cells by the common γ-chain cytokines IL-2, IL-7, IL-15, and IL-21 is associated with proliferation and is dependent on the phosphoinositide 3-kinase pathway.
abstract: T cell Ig mucin domain-containing molecule 3 (Tim-3) is a glycoprotein found on the surface of a subset of CD8(+) and Th1 CD4(+) T cells. Elevated expression of Tim-3 on virus-specific T cells during chronic viral infections, such as HIV-1, hepatitis B virus, and hepatitis C virus, positively correlates with viral load. Tim-3(+) cytotoxic T cells are dysfunctional and are unable to secrete effector cytokines, such as IFN-γ and TNF-α. In this study, we examined potential inducers of Tim-3 on primary human T cells. Direct HIV-1 infection of CD4(+) T cells, or LPS, found to be elevated in HIV-1 infection, did not induce Tim-3 on T cells. Tim-3 was induced by the common γ-chain (γc) cytokines IL-2, IL-7, IL-15, and IL-21 but not IL-4, in an Ag-independent manner and was upregulated on primary T cells in response to TCR/CD28 costimulation, as well as γc cytokine stimulation with successive divisions. γc cytokine-induced Tim-3 was found on naive, effector, and memory subsets of T cells. Tim-3(+) primary T cells were more prone to apoptosis, particularly upon treatment with galectin-9, a Tim-3 ligand, after cytokine withdrawal. The upregulation of Tim-3 could be blocked by the addition of a PI3K inhibitor, LY 294002. Thus, Tim-3 can be induced via TCR/CD28 costimulation and/or γc cytokines, likely through the PI3K pathway.
authors.affiliation: Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Shariq
authors.initials: S
authors.lastname: Mujib
authors.forename: R Brad
authors.initials: RB
authors.lastname: Jones
authors.forename: Calvin
authors.initials: C
authors.lastname: Lo
authors.forename: Nasra
authors.initials: N
authors.lastname: Aidarus
authors.forename: Kiera
authors.initials: K
authors.lastname: Clayton
authors.forename: Ali
authors.initials: A
authors.lastname: Sakhdari
authors.forename: Erika
authors.initials: E
authors.lastname: Benko
authors.forename: Colin
authors.initials: C
authors.lastname: Kovacs
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ostrowski
mesh_terms: D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D037161:Galectins / Q000276:immunology / Q000494:pharmacology; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D015851:Interleukin-7 / Q000276:immunology / Q000494:pharmacology; D007378:Interleukins / Q000276:immunology* / Q000494:pharmacology; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D009025:Morpholines / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000276:immunology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D000098546:Interleukin-21
chemical_list: D018106:CD28 Antigens; D002867:Chromones; D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C569274:IL15 protein, human; C508594:IL2 protein, human; C508605:IL7 protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D007378:Interleukins; C105032:LGALS9 protein, human; D008565:Membrane Proteins; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011948:Receptors, Antigen, T-Cell; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D058539:Phosphatidylinositol 3-Kinase; D000098546:Interleukin-21