Herpesvirus entry mediator promotes Th1 responses in the cornea during ocular HSV-1 infection

Abstract

Abstract Herpes simplex virus-1 (HSV-1) is a major cause of infectious blindness in the developed world. Ocular herpetic disease is characterized by persistent inflammation in the corneal tissue even after the virus has successfully been cleared, which causes irreversible damage to the cornea. It is unknown what molecular mechanisms drive chronic inflammation following ocular HSV-1 infection. Herpesvirus entry mediator (HVEM), a TNFR superfamily member, mediates both stimulatory and inhibitory signals in T cells by interacting with its functional ligands, LIGHT and B and T lymphocyte attenuator (BTLA). Mice lacking HVEM exhibit a significant decrease in Th1 cells, PMNs, and monocytes in the cornea 14 days post-intracorneal HSV-1 infection as well as a decrease in Th1 and Th17 cells in the draining lymph nodes. We hypothesize that HVEM contributes to exacerbation of ocular disease by stimulatory co-signaling through interaction with its ligands. We observe that LIGHT deficient (LIGHT−/−) and BTLA deficient (BTLA−/−) mice alone do not show significant difference in infiltrating immune cells or corneal pathology compared to wild type (WT) mice. Interestingly, mice lacking both BTLA and LIGHT (BTLA−/−LIGHT−/−) exhibit significant reduction in Th1 cells and improvement in corneal pathology. We show that stimulatory HVEM signaling mediated by both LIGHT and BTLA promotes chronic inflammation during ocular HSV-1 infection.