Meningeal lymphatic drainage promotes T cell responses against Toxoplasma gondii but is dispensable for parasite control in the brain
Curation statements for this article:-
Curated by eLife
Evaluation Summary:
This manuscript tackles the timely and interesting research question of whether meningeal lymphatic drainage is required for the control of brain infection with Toxoplasma gondii. It contains a sophisticated experimental approach using cutting-edge methods, it has an easy-to-follow narrative, and comes up with an interesting albeit negative finding which the authors even tried to explain by an additional set of experiments. Although there are some limitations and weaknesses of the paper in its present form it will certainly contribute to the growing body of literature on how the once "immune-privileged" CNS is protected against environmental challenges.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
- Immunology and Inflammation (eLife)
Abstract
The discovery of meningeal lymphatic vessels that drain the 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.
Article activity feed
-
-
Evaluation Summary:
This manuscript tackles the timely and interesting research question of whether meningeal lymphatic drainage is required for the control of brain infection with Toxoplasma gondii. It contains a sophisticated experimental approach using cutting-edge methods, it has an easy-to-follow narrative, and comes up with an interesting albeit negative finding which the authors even tried to explain by an additional set of experiments. Although there are some limitations and weaknesses of the paper in its present form it will certainly contribute to the growing body of literature on how the once "immune-privileged" CNS is protected against environmental challenges.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to …
Evaluation Summary:
This manuscript tackles the timely and interesting research question of whether meningeal lymphatic drainage is required for the control of brain infection with Toxoplasma gondii. It contains a sophisticated experimental approach using cutting-edge methods, it has an easy-to-follow narrative, and comes up with an interesting albeit negative finding which the authors even tried to explain by an additional set of experiments. Although there are some limitations and weaknesses of the paper in its present form it will certainly contribute to the growing body of literature on how the once "immune-privileged" CNS is protected against environmental challenges.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
-
Reviewer #1 (Public Review):
Lymphatic drainage of CNS antigens has received lots of attention recently due to the (re)discovery of dural meningeal lymphatics. The role of dural lymphatics in CNS antigen drainage has been shown to be important in several contexts (AD, glioma, etc.). Few studies have focused on their role in CNS infections so far. In their study, Kovacs et al. dissected the role of meningeal lymphatic drainage in T cell responses during chronic Toxoplasma gondii infection in mice. They first show that T.g. infection drives DC accumulation in the dura and CSF at 6 weeks post-infection, which matches with the replication peak of T.g. in the brain, and with T cell expansion/activation in the dCLN. This effect on T cells in the dCLN was abrogated upon surgical blockade of dural drainage. However, dural lymphatic blockade did …
Reviewer #1 (Public Review):
Lymphatic drainage of CNS antigens has received lots of attention recently due to the (re)discovery of dural meningeal lymphatics. The role of dural lymphatics in CNS antigen drainage has been shown to be important in several contexts (AD, glioma, etc.). Few studies have focused on their role in CNS infections so far. In their study, Kovacs et al. dissected the role of meningeal lymphatic drainage in T cell responses during chronic Toxoplasma gondii infection in mice. They first show that T.g. infection drives DC accumulation in the dura and CSF at 6 weeks post-infection, which matches with the replication peak of T.g. in the brain, and with T cell expansion/activation in the dCLN. This effect on T cells in the dCLN was abrogated upon surgical blockade of dural drainage. However, dural lymphatic blockade did not affect T.g. burden, nor CD4+ and CD8+ T cell number and IFNg production in the brain in the chronic phase. They finally show that during chronic infection, antigen-specific T cells are generated not only in the dCLN but also in the periphery (ILN), which could account for the presence of T cells in the brain after surgical blockade of the lymphatics.
This study is interesting and some aspects are clearly convincing, but some precisions have to be made. More importantly, with similar tools, key experiments (as explained in the last paragraph: icv infection or chronic peripheral parasite clearance, etc.) have to be generated to bring more impact to this study and could reveal a new role for dCLN T cells.
-
Reviewer #2 (Public Review):
In the present manuscript Kovacs et al. investigate the CNS specific immune response against Toxoplasma gondii infection and is building on the (re)discovery of meningeal lymphatic vessels that drain the CNS. As it has been shown in the context of brain cancer and recently also in a murine model of CNS infection with Japanese encephalitis virus, the authors hypothesise that CNS Ag drainage is required for functional immunosurveillance in the context of T. gondii infection of the CNS. As T. gondii commonly causes chronic infections of the brain with potentially life-threatening effects on the host, studying how control of this parasite is achieved by the interaction of the CNS with the immune system is of great relevance for the field of (neuro-)immunology. Therefore, the strengths of the manuscript are …
Reviewer #2 (Public Review):
In the present manuscript Kovacs et al. investigate the CNS specific immune response against Toxoplasma gondii infection and is building on the (re)discovery of meningeal lymphatic vessels that drain the CNS. As it has been shown in the context of brain cancer and recently also in a murine model of CNS infection with Japanese encephalitis virus, the authors hypothesise that CNS Ag drainage is required for functional immunosurveillance in the context of T. gondii infection of the CNS. As T. gondii commonly causes chronic infections of the brain with potentially life-threatening effects on the host, studying how control of this parasite is achieved by the interaction of the CNS with the immune system is of great relevance for the field of (neuro-)immunology. Therefore, the strengths of the manuscript are novelty and relevance but also the use of an impressive and adequate set of laborious state-of-the-art techniques. The narrative of the manuscript is easy to follow and straightforward. The weaknesses of the manuscript at its present form are the rather superficial and biased analysis of the APC compartment and the experimental setup used to test the main research hypothesis which potentially led to a bit "hasty" final conclusion of the paper. The authors report that blocking meningeal lymphatic drainage has no effect on parasite control which seems disappointing at first but is also a valid and relevant finding. However, the data supporting this conclusion are not very rigorous and the authors could have tried to ask whether the approach, time point, and readout are sufficient to support this conclusion or if they might have missed something. The flow cytometry part of the manuscript needs some fine tuning but most of the data are convincing enough to support the main claims of the authors. Although there are some limitations and weaknesses of the paper at its present form it will certainly increase our understanding of how the once "immune-privileged" CNS is protected against environmental challenges.
-
