Role of Tim-3/Galectin-9 Inhibitory Interaction In Viral Induced Immunopathology: Shifting The Balance Towards Regulators

摘要

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.