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Meningeal lymphatic drainage promotes T cell responses against Toxoplasma gondii but is dispensable for parasite control in the brain

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 promot...

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Autores principales: Kovacs, Michael A, Cowan, Maureen N, Babcock, Isaac W, Sibley, Lydia A, Still, Katherine, Batista, Samantha J, Labuzan, Sydney A, Sethi, Ish, Harris, Tajie H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9812409/
https://www.ncbi.nlm.nih.gov/pubmed/36541708
http://dx.doi.org/10.7554/eLife.80775
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author Kovacs, Michael A
Cowan, Maureen N
Babcock, Isaac W
Sibley, Lydia A
Still, Katherine
Batista, Samantha J
Labuzan, Sydney A
Sethi, Ish
Harris, Tajie H
author_facet Kovacs, Michael A
Cowan, Maureen N
Babcock, Isaac W
Sibley, Lydia A
Still, Katherine
Batista, Samantha J
Labuzan, Sydney A
Sethi, Ish
Harris, Tajie H
author_sort Kovacs, Michael A
collection PubMed
description 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.
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spelling pubmed-98124092023-01-05 Meningeal lymphatic drainage promotes T cell responses against Toxoplasma gondii but is dispensable for parasite control in the brain Kovacs, Michael A Cowan, Maureen N Babcock, Isaac W Sibley, Lydia A Still, Katherine Batista, Samantha J Labuzan, Sydney A Sethi, Ish Harris, Tajie H eLife Immunology and Inflammation 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. eLife Sciences Publications, Ltd 2022-12-21 /pmc/articles/PMC9812409/ /pubmed/36541708 http://dx.doi.org/10.7554/eLife.80775 Text en © 2022, Kovacs et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Immunology and Inflammation
Kovacs, Michael A
Cowan, Maureen N
Babcock, Isaac W
Sibley, Lydia A
Still, Katherine
Batista, Samantha J
Labuzan, Sydney A
Sethi, Ish
Harris, Tajie H
Meningeal lymphatic drainage promotes T cell responses against Toxoplasma gondii but is dispensable for parasite control in the brain
title Meningeal lymphatic drainage promotes T cell responses against Toxoplasma gondii but is dispensable for parasite control in the brain
title_full Meningeal lymphatic drainage promotes T cell responses against Toxoplasma gondii but is dispensable for parasite control in the brain
title_fullStr Meningeal lymphatic drainage promotes T cell responses against Toxoplasma gondii but is dispensable for parasite control in the brain
title_full_unstemmed Meningeal lymphatic drainage promotes T cell responses against Toxoplasma gondii but is dispensable for parasite control in the brain
title_short Meningeal lymphatic drainage promotes T cell responses against Toxoplasma gondii but is dispensable for parasite control in the brain
title_sort meningeal lymphatic drainage promotes t cell responses against toxoplasma gondii but is dispensable for parasite control in the brain
topic Immunology and Inflammation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9812409/
https://www.ncbi.nlm.nih.gov/pubmed/36541708
http://dx.doi.org/10.7554/eLife.80775
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