Dysregulated Tim-3 expression on natural killer cells is associated with increased Galectin-9 levels in HIV-1 infection
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RESEARCH
Open Access
Dysregulated Tim-3 expression on natural killer cells is associated with increased Galectin-9 levels in HIV-1 infection Stephanie Jost1, Uriel Y Moreno-Nieves1, Wilfredo F Garcia-Beltran1, Keith Rands1, Jeff Reardon1, Ildiko Toth1, Alicja Piechocka-Trocha1, Marcus Altfeld1,2 and Marylyn M Addo1*
Abstract Background: 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. Results: We 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. Conclusions: Our 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. Keywords: Tim-3, Gal-9, HIV-1, Innate immunity, NK cells
Background The human immunodeficiency virus type 1 (HIV-1) affects 34 million adults and children worldwide, and the ongoing spread of the epidemic resulted in about 2.5 million new infections and 1.7 million deaths in 2011 alone [1]. Novel approaches to prevent the transmission of HIV-1 are urgently needed, and whether manipulating innate immune effector cell function could be used as a strategy to enhance HIV-1 vaccine efficiency remains to be determined. Recent data suggest that incorporating components with the potential to harness the antiviral function of natural killer (NK) cells may represent an attractive option to improve future vaccine designs [2-13]. NK cells play an important role in containing viral replication in the very early stages of viral infections, * Correspondence: [email protected] 1 Ragon Institute of MGH, MIT and Harvard, 400 Technology Square, Cambridge, MA 02139, USA Full list of author information is available at the end of the article
and in shaping the subsequent adaptive immune response by interacting with other immune cells, including dendritic cells (DCs) and CD4+ T cells [14-17]. NK cell function is regulated by the integration of inhibitory and activating signals generated by an arsenal of cell surface recept
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