Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection

Abstract

Galectin-9 (Gal-9) is a tandem repeat-type member of the galectin family and is a ligand for T-cell immunoglobulin mucin domain 3 (Tim-3), a type-I glycoprotein that is persistently expressed on dysfunctional T cells during chronic infection. Studies in autoimmune diseases and chronic viral infections show that Tim-3 is a regulatory molecule that inhibits Th1 type immune responses. Here we show that soluble Gal-9 interacts with Tim-3 expressed on the surface of activated CD4 ؉ T cells and renders them less susceptible to HIV-1 infection and replication. The Gal-9/Tim-3 interaction on activated CD4 ؉ T cells, leads to down-regulation of HIV-1 coreceptors and up-regulation of the cyclin-dependent kinase inhibitor p21 (also known as cip-1 and waf-1). We suggest that higher expression of Tim-3 during chronic infection has evolved to limit persistent immune activation and associated tissue damage. These data demonstrate a novel mechanism for Gal-9/Tim-3 interactions to induce resistance of activated CD4 ؉ T cells to HIV-1 infection and suggest that Gal-9 may play a role in HIV-1 pathogenesis and could be used as a novel microbicide to prevent HIV-1 infection. (Blood. 2012;119(18):4192-4204) IntroductionProphylactic interventions against HIV-1 acquisition, such as vaccine and microbicide candidates, have not proved efficacious or even enhanced acquisition in previous human clinical trials. 1,2 Even the most promising vaccine to date, which involved a canarypox prime followed by a gp120 protein boost, only showed limited efficacy that waned over time. 3 More effective strategies that block initial HIV-1 acquisition at the site of exposure are required. Interestingly, deletion of 32 base pairs in the ccr5 gene 4 and selective up-regulation of p21 in CD4 ϩ T cells from elite controllers 5 render some individuals naturally resistant to HIV-1 infection. The mechanism(s) responsible for resistance of CD4 ϩ T cells to HIV-1 infection are not well known, but defining them is vital for designing prophylactic interventions.Galectin-9 (Gal-9), a member of the ␤-galactoside-binding animal lectin family, was originally characterized as an eosinophil chemoattractant. 6 Subsequent studies determined that it is a versatile immunomodulator involved in a wide range of biologic activities, such as cell adhesion and migration, proliferation and apoptosis, interaction of host cells with microbial pathogens, regulatory T-cell (Treg) differentiation and function, dendritic cell (DC) maturation, and antimicrobial immunity. 7-13 Gal-9 is expressed by eosinophils, endothelial cells, T lymphocytes, DCs, macrophages, lymphoid cells, Kupffer cells, intestinal epithelial cells, and vascular endothelial cells. 10,[14][15][16][17][18][19] Wide distribution of Gal-9 on host cells demonstrates an important but complex role for this lectin, whose biologic effects are exerted by 2 receptors with distinct, and often opposing effects: TIM-3 (T-cell immunoglobulin [Ig] and mucin domain-containing molecule 3) 20 and cell surface protein disulfide isomerase...

Galectin-9 Functionally Impairs Natural Killer Cells in Humans and Mice

“…Gal-9 is highly expressed in tissues of the immune system, including bone marrow, lymph nodes, liver, thymus, and spleen, and patients with chronic viral infection have elevated circulating levels (3,4). Gal-9 has complex immunomodulatory roles involving effector cells of both innate and adaptive immunity.…”

“…Gal-9 is widely distributed throughout various tissues, being particularly abundant in the liver (2). We have demonstrated that Gal-9 circulates at very high levels in the serum, and its hepatic expression is significantly increased in patients with chronic hepatitis C virus (HCV) compared to normal controls (3), and others have found high levels of Gal-9 in patients with HIV (4). Gal-9 interacts with various ligands, the best characterized of which is the T cell immunoglobulin mucin 3 (Tim-3) cell surface molecule, widely expressed on innate and adaptive immune cells (5).…”

Human Cytomegalovirus Upregulates Expression of the Lectin Galectin 9 via Induction of Beta Interferon

“…Indeed, individuals infected with hepatitis C virus (HCV), HIV-1, dengue virus, and influenza virus have higher serum levels of Gal-9 (6,(22)(23)(24), yet the mechanism responsible for such increases has not been identified. Given the critical role of type I IFNs in controlling viral infections, it is tempting to speculate that IFN-␤ may be an essential driver of Gal-9 upregulation.…”

“…Gal-9 can play an important role in virus life cycles. It modulates human immunodeficiency virus type 1 (HIV-1) entry (6,7), while Gal-9-knockout mice exhibit more potent antiviral T-cell responses than wild-type mice (8,9), and infection with Epstein-Barr virus (EBV) modulates Gal-9 expression to evade immune clearance, inducing apoptosis of EBV-specific CD4 ϩ T cells (10,11). We investigated the expression of Gal-9 in the context of HCMV infection both in vivo and in vitro, identifying a novel, virally induced mechanism to promote Gal-9 expression.…”

Galectin-9 Changes Its Function to Maintain Homeostasis

“…Furthermore, we showed that Gal-9 binding to Tim-3 renders activated human CD4 + T cells less susceptible to HIV-1 infection (46). Since Gal-9 can inhibit infection by influenza virus, it is suggested that Gal-9 is also a useful therapy for HIV infection.…”