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Role of Tim-3/Galectin-9 Inhibitory Interaction in Viral-Induced Immunopathology: Shifting the Balance toward Regulators¹

Sharvan Sehrawat^*, Amol Suryawanshi^*, Mitsuomi Hirashima and Barry T. Rouse^2,*

^* Comparative and Experimental Medicine, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN 37996; and Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa, Japan

Controlling chronic immunoinflammatory diseases such as lesions in the eye caused by infection with HSV represents a 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 (T cell Ig and mucin-3) that is expressed by activated but not naive 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 mAb 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 stromal keratitis 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 and 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 stromal keratitis pathogenesis. Our results indicate that galectin-9 therapy may represent a useful approach to control HSV-induced lesions, the most common cause of infectious blindness in the Western world.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institute of Allergy and Infectious Diseases Grant AI 063365 and National Institutes of Health Grant EY 05093.

² Address correspondence and reprint requests to Dr. Barry T. Rouse or Dr. Sharvan Sehrawat, M409, Walters Life Sciences Building, Department of Pathobiology, The University of Tennessee, 1414 Cumberland Avenue, Knoxville, TN 37996-0845. E-mail addresses: btr{at}utk.edu or ss1{at}utk.edu

³ Abbreviations used in this paper: HSK, herpetic stromal keratitis; DLN, draining lymph node; dpi, days postinfection; HPRT, hypoxanthine phosphoribosyltransferase; MOI, multiplicity of infection; SK, stromal keratitis; TIM-3, T cell Ig and mucin-3; Treg, regulatory T cell; VEGF, vascular endothelial growth factor.