title: TIM-3 does not act as a receptor for galectin-9.
abstract: T cell immunoglobulin and mucin protein 3 (TIM-3) is a type I cell surface protein that was originally identified as a marker for murine T helper type 1 cells. TIM-3 was found to negatively regulate murine T cell responses and galectin-9 was described as a binding partner that mediates T cell inhibitory effects of TIM-3. Moreover, it was reported that like PD-1 the classical exhaustion marker, TIM-3 is up-regulated in exhausted murine and human T cells and TIM-3 blockade was described to restore the function of these T cells. Here we show that the activation of human T cells is not affected by the presence of galectin-9 or antibodies to TIM-3. Furthermore, extensive studies on the interaction of galectin-9 with human and murine TIM-3 did not yield evidence for specific binding between these molecules. Moreover, profound differences were observed when analysing the expression of TIM-3 and PD-1 on T cells of HIV-1-infected individuals: TIM-3 was expressed on fewer cells and also at much lower levels. Furthermore, whereas PD-1 was preferentially expressed on CD45RA(-)CD8 T cells, the majority of TIM-3-expressing CD8 T cells were CD45RA(+). Importantly, we found that TIM-3 antibodies were ineffective in increasing anti-HIV-1 T cell responses in vitro, whereas PD-L antibodies potently reverted the dysfunctional state of exhausted CD8 T cells. Taken together, our results are not in support of an interaction between TIM-3 and galectin-9 and yield no evidence for a functional role of TIM-3 in human T cell activation. Moreover, our data indicate that PD-1, but not TIM-3, is a promising target to ameliorate T cell exhaustion.
authors.affiliation: Division of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Judith
authors.initials: J
authors.lastname: Leitner
authors.forename: Armin
authors.initials: A
authors.lastname: Rieger
authors.forename: Winfried F
authors.initials: WF
authors.lastname: Pickl
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zlabinger
authors.forename: Katharina
authors.initials: K
authors.lastname: Grabmeier-Pfistershammer
authors.forename: Peter
authors.initials: P
authors.lastname: Steinberger
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D045744:Cell Line, Tumor; D002470:Cell Survival; D037161:Galectins / Q000276:immunology / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism*; D015497:HIV-1; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D061026:Programmed Cell Death 1 Receptor; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105032:LGALS9 protein, human; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011956:Receptors, Cell Surface
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