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.
Highlights
Inhibitory costimulatory signals play a decisive role in the outcome of T cell responses and there is an ever-growing number of pathways that have been implicated in such processes
Inhibitory costimulatory receptors are a hallmark of exhausted T cells, which accumulate during chronic infection with viruses like HIV-1
Galectin-9 was reported as an inhibitory ligand for T cell immunoglobulin and mucin domain 3 (TIM-3) on murine T cells, but it was not known whether galectin-9 has a role in human T cell activation processes
Summary
Inhibitory costimulatory signals play a decisive role in the outcome of T cell responses and there is an ever-growing number of pathways that have been implicated in such processes. It has been acknowledged that inhibitory pathways significantly contribute to the exhausted state of T cells, which results from persistent antigen stimulation in chronic virus infections or cancer. The inhibitory PD-1 was identified as a marker for such dysfunctional T cells and blockade of PD-1 signals - in most cases realized with antibodies to PD-L1 - was shown to revert the dysfunctional state of exhausted T cells [2,3,4]. Several studies indicate that among these molecules, the T cell immunoglobulin and mucin domain 3 (TIM-3) has an important role in maintaining the dysfunctional state of exhausted T cells, as TIM-3 blockade restored proliferation and cytokine production upon antigenic challenge in these cells [10,11,12,13]. It has been suggested that blocking TIM-3/TIM-3 ligand interactions might be of clinical utility by restoring the function of virus or tumour-specific T cells
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