Meningeal lymphatic drainage promotes T cell responses againstToxoplasma gondiibut is dispensable for parasite control in the brain

Abstract

ABSTRACTThe discovery of meningeal lymphatic vessels that drain the central nervous system (CNS) has prompted new insights into how neuroinflammation develops. In this study, we examined how T cell responses against CNS-derived antigen develop in the context of infection. We found that meningeal lymphatic drainage promotes CD4+and CD8+T cell responses against the neurotropic parasiteToxoplasma gondii, and we discovered changes in the antigen-presenting cell compartment of the dural meninges that potentially support this process. Indeed, compared to uninfected controls, mice chronically infected withT. gondiidisplayed a ten-fold increase in the total number of dendritic cells in the dural meninges. These cells upregulated MHC class II, CD80, and CD86 expression, sampled cerebrospinal fluid-derived protein, and were detected within meningeal lymphatic vessels in greater numbers during infection. Disrupting meningeal lymphatic drainage via ligation surgery resulted in reduced dendritic cell number and maturation in the deep cervical lymph nodes and impaired CD4+and CD8+T cell activation, proliferation, and IFN-γ production at this site. Surprisingly, parasite-specific T cell responses in the brain remained intact following ligation, which may be due to activation of T cells at alternative sites during chronic infection, including lymph nodes that drain non-CNS tissue. Collectively, our work reveals that CNS lymphatic drainage supports the development of peripheral T cell responses againstT. gondiibut is nonetheless dispensable for host protection of the brain.