Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis

Abstract

Central nervous system infection of mice with lymphocytic choriomeningitis virus (LCMV) is a commonly used model for chronic viral disease. LCMV-specific cytotoxic T lymphocytes (CD8+ T cells) are involved in the condition, but their role in pathogenesis is unclear. The 'cell killing' activity of these cells might be expected to be part of the story, but a new study using two-photon fluorescence microscopy suggests this is not the case. Rather, cytotoxic T lymphocytes can be seen recruiting monocytes and neutrophils to the meninges at the blood–brain border. The blood vessels there become leaky and fatal seizures result. This raises new questions, including the mechanism of cell recruitment and how the cells produce such damage in meningitis, and suggests several new drug targets. CD8+ T cells are shown to induce vascular leakage in acute viral meningitis not by killing specific target cells, but by recruiting neutrophils and monocytes to the blood–brain barrier. Lymphocytic choriomeningitis virus1 infection of the mouse central nervous system (CNS) elicits fatal immunopathology through blood–brain barrier breakdown2 and convulsive seizures3. Although lymphocytic-choriomeningitis-virus-specific cytotoxic T lymphocytes (CTLs) are essential for disease4, their mechanism of action is not known. To gain insights into disease pathogenesis, we observed the dynamics of immune cells in the meninges by two-photon microscopy. Here we report visualization of motile CTLs and massive secondary recruitment of pathogenic monocytes and neutrophils that were required for vascular leakage and acute lethality. CTLs expressed multiple chemoattractants capable of recruiting myelomonocytic cells. We conclude that a CD8+ T-cell-dependent disorder can proceed in the absence of direct T-cell effector mechanisms and rely instead on CTL-recruited myelomonocytic cells.