Galectin-9/TIM-3 Interaction Regulates Virus-Specific Primary and Memory CD8+ T Cell Response

Abstract

In this communication, we demonstrate that galectin (Gal)-9 acts to constrain CD8+ T cell immunity to Herpes Simplex Virus (HSV) infection. In support of this, we show that animals unable to produce Gal-9, because of gene knockout, develop acute and memory responses to HSV that are of greater magnitude and better quality than those that occur in normal infected animals. Interestingly, infusion of normal infected mice with α-lactose, the sugar that binds to the carbohydrate-binding domain of Gal-9 limiting its engagement of T cell immunoglobulin and mucin (TIM-3) receptors, also caused a more elevated and higher quality CD8+ T cell response to HSV particularly in the acute phase. Such sugar treated infected mice also had expanded populations of effector as well as memory CD8+ T cells. The increased effector T cell responses led to significantly more efficient virus control. The mechanisms responsible for the outcome of the Gal-9/TIM-3 interaction in normal infected mice involved direct inhibitory effects on TIM-3+ CD8+ T effector cells as well as the promotion of Foxp3+ regulatory T cell activity. Our results indicate that manipulating galectin signals, as can be achieved using appropriate sugars, may represent a convenient and inexpensive approach to enhance acute and memory responses to a virus infection.

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).…”

Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection

“…Data suggest that Tim-3/Gal-9 interactions in the context of microbial infection leads to a dual outcome, either enhancement of innate immunity and clearance of the pathogen 10 or termination of adaptive immunity and reduction in inflammationrelated tissue damage. 26 This may be related to the fact that Tim-3 ligation on DCs and macrophages leads to their activation, whereas Tim-3 ligation on T cells results in their inhibition. 13 Although many Gal-9 functions, in particular on T cells, are regulated via Tim-3 binding, various Tim-3-independent effects of Gal-9 have been reported.…”

Human Cytomegalovirus Upregulates Expression of the Lectin Galectin 9 via Induction of Beta Interferon

“…Gal-9 can play an important role in virus life cycles. It modulates human immunodeficiency virus type 1 (HIV-1) entry (6,7), while Gal-9-knockout mice exhibit more potent antiviral T-cell responses than wild-type mice (8,9), and infection with Epstein-Barr virus (EBV) modulates Gal-9 expression to evade immune clearance, inducing apoptosis of EBV-specific CD4 ϩ T cells (10,11). We investigated the expression of Gal-9 in the context of HCMV infection both in vivo and in vitro, identifying a novel, virally induced mechanism to promote Gal-9 expression.…”