Galectin-9/TIM-3 interaction regulates virus-specific primary and memory CD8 T cell response

• Published in: PLoS pathogens 2010-05, Vol.6 (5), p.e1000882-e1000882
• Main Authors: Sehrawat, Sharvan, Reddy, Pradeep B J, Rajasagi, Naveen, Suryawanshi, Amol, Hirashima, Mitsuomi, Rouse, Barry T
• Format: Article
• Language: English
• Subjects: Acute-Phase Reaction - immunology; Acute-Phase Reaction - virology; Animals; Apoptosis - immunology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - virology; Female; Forkhead Transcription Factors - metabolism; Galectins - genetics; Galectins - metabolism; Hepatitis A Virus Cellular Receptor 2; Herpes Simplex - immunology; Herpes Simplex - metabolism; Immune system; Immunologic Memory - immunology; Immunology; Immunology/Immunity to Infections; Infections; Lactose - immunology; Lactose - metabolism; Lactose - pharmacology; Lymphoid Tissue - immunology; Lymphoid Tissue - virology; Mice; Mice, Inbred C57BL; Mice, Knockout; Proteins; Receptors, Virus - metabolism; T cell receptors; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - virology; Up-Regulation - immunology; Viral Load - immunology; Viral Vaccines
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1000882

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 alpha-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.