The bitter side of sweet: the role of Galectin-9 in immunopathogenesis of viral infections

Abstract

In recent years, a critical role for β-galactoside-binding protein, Galectin-9 (Gal-9) has emerged in infectious disease, autoimmunity, and cancer. It 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 viral infections. Gal-9 exerts its pivotal immunomodulatory effects by inducing apoptosis or suppressing effector functions via engagement with its receptor, Tim-3. Recent studies report elevation of circulating Gal-9 in humans infected with different viral infections. Interaction of soluble Gal-9 with Tim-3 expressed on the surface of activated CD4+ T cells renders them less susceptible to HIV-1 infection, while enhanced HIV infection occurs when Gal-9 interacts with a different receptor than Tim-3. This indicates the versatile role of Gal-9 in viral pathogenesis. For instance, higher expression of Tim-3 during chronic viral infection and elevation of plasma Gal-9 may have evolved to limit persistent immune activation and pathogenic T cells activity. In contrast, Gal-9 can suppress the effectiveness of immunity against viral infections. In agreement, Gal-9 knockout mice mount a more robust and vigorous virus-specific immune response in acute and chronic viral infections resulting in rapid viral clearance. In line with this observation, blocking Gal-9 signals to Tim-3-expressing T cells result in improved immune responses. Here we review the biological and immunological properties of Gal-9 in viral infections (HIV, HCV, HBV, HSV, CMV, influenza, and dengue virus). Manipulating Gal-9 signals may have immunotherapeutic potential and could represent an alternative approach for improving immune responses to viral infections/vaccines.

Prognostic Role of High Gal-9 Expression in Solid Tumours: a Meta-Analysis

“…Recent studies indicate that the C-CRD of Gal-9 is responsible for receptor recognition and T-cell death, while the N-CRD is more potent in activation of dendritic cells (DCs) [26]. A critical role of Gal-9 has been reported in infectious disease, autoimmune disease and cancer [27]. One identified binding partner of various glycoproteins interacting with Gal-9 is Tim-3, which is expressed on specific T-cell subsets and cells of the innate immune system, including macrophages, monocytes, and DCs [8, 28].…”

Galectin‐9 and CXCL10 as Biomarkers for Disease Activity in Juvenile Dermatomyositis: A Longitudinal Cohort Study and Multicohort Validation

“…Recently, in a cross-sectional cohort of patients with juvenile DM, we demonstrated that 3 proteins, galectin-9, CXCL10, and tumor necrosis factor receptor type II, can distinguish between juvenile DM patients with active disease and those in remission, with galectin-9 and CXCL10 being the most discriminative markers (26,27). CXCL10 and galectin-9 can be produced by a variety of cells, both immune and nonimmune, upon stimulation with interferons (28,29). CXCL10 has been recognized as a biomarker in several human autoimmune diseases, including myositis (29)(30)(31)(32)(33), whereas galectin-9 has been investigated mainly as a biomarker in cancer and viral infections (28,34).…”

“…CXCL10 and galectin-9 can be produced by a variety of cells, both immune and nonimmune, upon stimulation with interferons (28,29). CXCL10 has been recognized as a biomarker in several human autoimmune diseases, including myositis (29)(30)(31)(32)(33), whereas galectin-9 has been investigated mainly as a biomarker in cancer and viral infections (28,34). Reports on the role of galectin-9 in autoimmunity are conflicting, suggesting either an attenuating or an aggravating effect on autoimmune manifestations in experimental models (35,36).…”

Role of Lgals9 Deficiency in Attenuating Nephritis and Arthritis in BALB/c Mice in a Pristane‐Induced Lupus Model

“…A more robust and vigorous virus‐specific immune response to acute and chronic viral infections is mounted in Gal‐9–deficient mice, resulting in rapid viral clearance. Thus, antagonism of Gal‐9 signaling may be beneficial for the prevention of various infections, including viral infection , in patients with SLE.…”