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...