Role of Tim-3/Galectin-9 Inhibitory Interaction in Viral-Induced Immunopathology: Shifting the Balance toward Regulators

Abstract

Controlling chronic immunoinflammatory diseases such as lesions in eye caused by infection with herpes simplex virus (HSV) represents therapeutic challenge. Since CD4+ T cells are the primary orchestrators of lesions, targeting activated CD4+ T cell subsets and increasing the representation of cells that express regulatory function would be a logical therapeutic approach. We show that this outcome can be achieved by therapy, systemic or local, with the lectin-family member galectin-9. This molecule, which is a natural product of many cell types, acts as a ligand to the inhibitory molecule TIM-3 that is expressed by activated but not naïve T cells. We show that 50% or more of T cells in ocular lesions caused by HSV in mice express TIM-3 and that blocking signals from its natural ligand with a monoclonal antibody results in more severe lesions. More importantly the provision of additional galectin-9, either systemically or more effectively by local subconjuctival administration, diminished the severity of SK lesions as well as the extent of corneal neovascularization. Multiple mechanisms were involved in inhibitory effects. These included apoptosis of the orchestrating effector T cells with consequent reduction of proinflammatory cytokines, an increase in the representation of two separate subtypes of regulatory cells as well as inhibitory effects on the production of molecules involved in neovascularization, an essential component of SK pathogenesis. Our results indicate that galectin-9 therapy may represent a useful approach to control HSV induced lesions, the commonest cause of infectious blindness in the Western World.

Immunization with Different Viral Antigens Alters the Pattern of T Cell Exhaustion and Latency in Herpes Simplex Virus Type 1-Infected Mice

“…More recently, CD4 ϩ Tim-3 ϩ T cells were implicated in primary HSV-1 infection, and by altering the interaction of Tim-3 with its ligand, the authors could produce therapeutic effects on ocular lesions (51,52).…”

T cell immunoglobulin and mucin protein-3 (Tim-3)/Galectin-9 interaction regulates influenza A virus-specific humoral and CD8 T-cell responses

“…Tissue damage is limited by several counterinflammatory events that act to functionally inhibit or destroy damaging cells as occurs when Gal-9 binds to one of its receptors, Tim-3 (14). Counterinflammatory events benefit the host in some chronic inflammatory processes (10, 19), autoimmunity, and some viral immunopathological lesions (11,14) but, as we demonstrate in this report, Tim-3/Gal-9 interactions can also act to limit the effectiveness of immunity to acute infectious agents, such as influenza virus. Accordingly, we show that mice lacking the ability to produce Gal-9 because of gene knockout generate more robust antiviral T-cell responses, more rapid antibody responses, and control intranasal infection more effectively than WT animals.…”

“…These include some cytokines (7), groups of molecules derived from omega-3 polyunsaturated fatty acids (8), as well as some of the carbohydrate binding proteins of the galectin family (9). Galectin-9 (Gal-9), for example, upon binding to Tim-3 on T cells acts to limit the extent of immunopathological lesions in autoimmunity (10) as well as in some chronic infections (11)(12)(13). In the present study, we investigated whether the inhibitory effects of Gal-9 on Tim-3-expressing cells could influence the outcome of acute infection with influenza A virus (IAV).…”

Specific Dietary Oligosaccharides Increase Th1 Responses in a Mouse Respiratory Syncytial Virus Infection Model

“…Galectins have been shown to control immune homeostasis and inflammation. Galectin-9 -Tim-3 interactions regulate virus-specific primary and memory CD8 ϩ T cell responses in herpes simplex virus infections and promote the induction of regulatory T cells (42,43).…”