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

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.
Author Summary Adaptive immune responses to foreign antigens require precise regulation, otherwise excessive bystander damage to host tissues may occur and responses to other antigens could be compromised. Some galectin proteins binding to receptors on cells of the immune system form part of the regulatory system, although this topic has received scant attention as it relates to antiviral control. In this report, we evaluate the role of the galectin-9/TIM-3 receptor pathway at regulating acute and memory CD8+ T cell responses to herpes simplex virus (HSV) infection. We demonstrate that CD8+ T cell responses to HSV were significantly increased in magnitude and improved in quality in mice unable to produce galectin-9 because of gene knockout compared to wild type controls. Furthermore, inhibiting the galectin-9 mediated response to TIM-3 using the sugar alpha-lactose that binds to Gal-9 led to a similar response pattern. The influence of galectin-9 to constrain CD8+ T cell responses involved direct inhibitory effects on the T effectors as well as the promotion of regulatory T cell responses. Our results indicate that manipulating the interaction of galectins with receptors using simple sugars may represent a convenient and inexpensive approach to enhance T cell responses to virus infections, and could prove useful to increase the efficacy of some vaccines.