The role of meningeal lymphatics in viral meningitis

Abstract

Discovery of the meningeal lymphatic vessels in the brain meninges (coverings of the brain) led to the hypothesis that they carry macromolecules and immune cells from cerebrospinal fluid (CSF) to cervical lymph nodes (cLN). Our new findings suggest that the lymphatic system controls immune responses through guiding antigen-presenting cells, such as dendritic cells (DC) from the meninges to draining lymph nodes. By using surgical and pharmacological methods to interfere with meningeal lymphatic vessels, we found lymphatics to serve as a major conduit by which DC leave the meninges, traffic to cLN and promote the generation of antigen-specific T cells. Inflammation-induced migration of DC is primarily regulated through a CC-chemokine receptor 7 (CCR7) dependent pathway. Co-injection of equal parts of differentially labeled CCR7-deficient and wild-type (WT) DCs into the CSF of the brain did allow translocation of CCR7-competent DC into the T cell zone of the draining lymph nodes but not CCR7−/− DC. Subsequently, antigenic stimulation by CCR7−/− DC did not induce a T cells response in the cLN, whereas WT DC enforced the majority of antigen-specific T cells to proliferate and increase their effective trafficking through integrin expression. To gain insights into how T cell responses are elicited when the meninges are infected with a virus, we currently set out to understand the lymphatics function in a mouse model of virus-induced meningitis. Injection of Lymphocytic choriomeningitis virus into the CSF induces rapid, uniform and fatal inflammation that is dependent on the generation of viral specific CD8+ T cells and potentially the exit of migratory DC through meningeal lymphatic vessels.