TIM-3 does not act as a receptor for galectin-9

PLoS Pathog. 2013 Mar;9(3):e1003253. doi: 10.1371/journal.ppat.1003253. Epub 2013 Mar 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Blocking / pharmacology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / virology
  • Cell Line, Tumor
  • Cell Survival
  • Galectins / immunology
  • Galectins / metabolism*
  • HIV Infections / immunology
  • HIV Infections / metabolism*
  • HIV-1
  • Hepatitis A Virus Cellular Receptor 2
  • Humans
  • Lymphocyte Activation
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism*
  • Mice
  • Programmed Cell Death 1 Receptor
  • Receptors, Cell Surface / immunology
  • Receptors, Cell Surface / metabolism*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*

Substances

  • Antibodies, Blocking
  • Galectins
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • LGALS9 protein, human
  • Membrane Proteins
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Cell Surface

Grant support

This work was supported by the Austrian Science Fund (www.fwf.ac.at; grant 21964-B20), and a grant from the Austrian Society for Dermatology and Venereology (www.oegdv.at/cms) to KGP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.