Dysregulated Tim-3 expression on natural killer cells is associated with increased Galectin-9 levels in HIV-1 infection

Stephanie Jost,Alicja Piechocka-Trocha,Ildiko Toth,Marylyn M Addo,Jeff Reardon,Marcus Altfeld,Keith Rands,Wilfredo F Garcia-Beltran,Uriel Y Moreno-Nieves

doi:10.1186/1742-4690-10-74

Stephanie Jost, Alicja Piechocka-Trocha + Show 7 more

Open Access

https://doi.org/10.1186/1742-4690-10-74

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Abstract

BackgroundNatural killer (NK) cells constitutively express high levels of Tim-3, an immunoregulatory molecule recently proposed to be a marker for mature and functional NK cells. Whether HIV-1 infection modulates the expression of Tim-3 on NK cells, or the levels of its ligand Galectin-9 (Gal-9), and how signaling through these molecules affects the NK cell response to HIV-1 remains inadequately understood.ResultsWe analyzed Tim-3 and Gal-9 expression in a cohort of 85 individuals with early and chronic HIV-1 infection, and in 13 HIV-1 seronegative control subjects. HIV-1 infection was associated with reduced expression of Tim-3 on NK cells, which was normalized by HAART. Plasma concentrations of Gal-9 were higher in HIV-1-infected individuals than in healthy individuals. Interestingly, Gal-9 expression in immune cells was significantly elevated in early infection, with monocytes and dendritic cells displaying the highest expression levels, which correlated with HIV-1 viral loads. In vitro, Gal-9 triggered Tim-3 downregulation on NK cells as well as NK cell activation.ConclusionsOur data suggest that high expression levels of Gal-9 during early HIV-1 infection can lead to enhanced NK cell activity, possibly allowing for improved early control of HIV-1. In contrast, persistent Gal-9 production might impair Tim-3 activity and contribute to NK cell dysfunction in chronic HIV-1 infection.

Highlights

Natural killer (NK) cells constitutively express high levels of T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3), an immunoregulatory molecule recently proposed to be a marker for mature and functional NK cells
As progressive human immunodeficiency virus type 1 (HIV-1) infection leads to the accumulation of dysfunctional NK cells [41,42], we first examined whether surface expression of Tim-3 protein on NK cells was altered in individuals at different stages of HIV-1 negative (HIV-)1 infection when compared to healthy subjects (Table 1)
As demonstrated in previous studies, our data highlight a high degree of variation between the frequencies of Tim-3-expressing NK cells in HIV-1 negative individuals [21] (Figure 1)

Summary

Introduction

Natural killer (NK) cells constitutively express high levels of Tim-3, an immunoregulatory molecule recently proposed to be a marker for mature and functional NK cells. Whether HIV-1 infection modulates the expression of Tim-3 on NK cells, or the levels of its ligand Galectin-9 (Gal-9), and how signaling through these molecules affects the NK cell response to HIV-1 remains inadequately understood. NK cells play an important role in containing viral replication in the very early stages of viral infections, It has recently been described that NK cells constitutively express high levels of T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) [19,20,21]. While Tim-3 has been extensively studied on T cells, much less is known about the impact of Tim-3-mediated signaling on NK cell responses, notably in the context of viral infections

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