Meningeal lymphatic drainage promotes T cell responses against Toxoplasma gondii but is dispensable for parasite control in the brain
- University of Virginia, United States
Abstract
The discovery of meningeal lymphatic vessels that drain the central nervous system (CNS) has prompted new insights into how immune responses develop in the brain. 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 parasite Toxoplasma gondii in mice, and we observed changes in the dendritic cell compartment of the dural meninges that may support this process. Indeed, we found that mice chronically, but not acutely, infected with T. gondii exhibited a significant expansion and activation of type 1 and type 2 conventional dendritic cells (cDC) in the dural meninges. cDC1s and cDC2s were both capable of sampling cerebrospinal fluid (CSF)-derived protein and were found to harbor processed CSF-derived protein in the draining deep cervical lymph nodes. Disrupting meningeal lymphatic drainage via ligation surgery led to a reduction in CD103+ cDC1 and cDC2 number in the deep cervical lymph nodes and caused an impairment in cDC1 and cDC2 maturation. Concomitantly, lymphatic vessel ligation impaired CD4+ and CD8+ T cell activation, proliferation, and IFN‑γ production at this site. Surprisingly, however, parasite-specific T cell responses in the brain remained intact following ligation, which may be due to concurrent activation of T cells at non-CNS-draining sites during chronic infection. Collectively, our work reveals that CNS lymphatic drainage supports the development of peripheral T cell responses against T. gondii but remains dispensable for immune protection of the brain.
Data availability
All data generated and analyzed during this study are included in the manuscript and supporting figures. Source data has been provided for Figures 2c-f.
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Author details
Funding
National Institutes of Health (R01NS112516)
- Tajie H Harris
University of Virginia (Pinn Scholars Award)
- Tajie H Harris
National Institutes of Health (R21NS128551)
- Tajie H Harris
National Institutes of Health (F30AI154740)
- Michael A Kovacs
National Institutes of Health (T32AI007496)
- Michael A Kovacs
- Maureen N Cowan
- Isaac W Babcock
National Institutes of Health (T32GM007267)
- Michael A Kovacs
National Institutes of Health (T32AI007046)
- Samantha J Batista
National Institutes of Health (T32GM008328)
- Katherine Still
National Institutes of Health (R01NS091067)
- Tajie H Harris
National Institutes of Health (R56NS106028)
- Tajie H Harris
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were approved by the Institutional Animal Care and Use Committee at the University of Virginia under protocol number 3968. When surgeries were performed on mice, mice were anesthetized using a solution containing ketamine (100 mg/kg) and xylazine (10 mg/kg) diluted in saline, and to minimize pain post-surgery mice were treated with ketoprofen (2 mg/kg).
Copyright
© 2022, Kovacs et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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