1. Immunology and Inflammation
  2. Microbiology and Infectious Disease

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

  1. Michael A Kovacs
  2. Maureen N Cowan
  3. Isaac W Babcock
  4. Lydia A Sibley
  5. Katherine Still
  6. Samantha J Batista
  7. Sydney A Labuzan
  8. Ish Sethi
  9. Tajie H Harris  Is a corresponding author
  1. University of Virginia, United States
https://doi.org/10.7554/eLife.80775
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Cite this article
  1. Michael A Kovacs
  2. Maureen N Cowan
  3. Isaac W Babcock
  4. Lydia A Sibley
  5. Katherine Still
  6. Samantha J Batista
  7. Sydney A Labuzan
  8. Ish Sethi
  9. Tajie H Harris
(2022)
Meningeal lymphatic drainage promotes T cell responses against Toxoplasma gondii but is dispensable for parasite control in the brain
eLife 11:e80775.
https://doi.org/10.7554/eLife.80775
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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.

Article and author information

Author details

  1. Michael A Kovacs

    Department of Neuroscience, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4298-9609

  2. Maureen N Cowan

    Department of Neuroscience, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Isaac W Babcock

    Department of Neuroscience, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Lydia A Sibley

    Department of Neuroscience, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Katherine Still

    Department of Neuroscience, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Samantha J Batista

    Department of Neuroscience, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Sydney A Labuzan

    Department of Neuroscience, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Ish Sethi

    Department of Neuroscience, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Tajie H Harris

    Department of Neuroscience, University of Virginia, Charlottesville, United States
    For correspondence
    tajieharris@virginia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1355-2109

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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  1. Michael A Kovacs
  2. Maureen N Cowan
  3. Isaac W Babcock
  4. Lydia A Sibley
  5. Katherine Still
  6. Samantha J Batista
  7. Sydney A Labuzan
  8. Ish Sethi
  9. Tajie H Harris
(2022)
Meningeal lymphatic drainage promotes T cell responses against Toxoplasma gondii but is dispensable for parasite control in the brain
eLife 11:e80775.
https://doi.org/10.7554/eLife.80775

Share this article

https://doi.org/10.7554/eLife.80775

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