Functional characterization of the dural sinuses as a neuroimmune interface

  • Cell. 2021 Feb 18;184(4):1000-1016.e27. doi: 10.1016/j.cell.2020.12.040.
Justin Rustenhoven  1 ,  Antoine Drieu  2 ,  Tornike Mamuladze  2 ,  Kalil Alves de Lima  2 ,  Taitea Dykstra  2 ,  Morgan Wall  3 ,  Zachary Papadopoulos  4 ,  Mitsuhiro Kanamori  2 ,  Andrea Francesca Salvador  5 ,  Wendy Baker  3 ,  Mackenzie Lemieux  6 ,  Sandro Da Mesquita  7 ,  Andrea Cugurra  8 ,  James Fitzpatrick  9 ,  Sanja Sviben  10 ,  Ross Kossina  10 ,  Peter Bayguinov  10 ,  Reid R Townsend  11 ,  Qiang Zhang  11 ,  Petra Erdmann-Gilmore  11 ,  Igor Smirnov  2 ,  Maria-Beatriz Lopes  12 ,  Jasmin Herz  2 ,  Jonathan Kipnis  13
Affiliations
  • 1. Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA. Electronic address: [email protected].
  • 2. Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • 3. Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
  • 4. Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Neuroscience Graduate Program, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • 5. Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA.
  • 6. Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Medical Scientist Training Program (MSTP), School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • 7. Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • 8. Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Gutenberg Research Fellowship Group of Neuroimmunology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn(2)), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
  • 9. Washington University Center for Cellular Imaging, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Departments of Neuroscience and Cell Biology and Physiology, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • 10. Washington University Center for Cellular Imaging, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • 11. Department of Medicine, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • 12. Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
  • 13. Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Neuroscience Graduate Program, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA; Gutenberg Research Fellowship Group of Neuroimmunology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn(2)), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. Electronic address: [email protected].
PMID: 33508229 DOI: 10.1016/j.cell.2020.12.040
Abstract

Despite the established dogma of central nervous system (CNS) immune privilege, neuroimmune interactions play an active role in diverse neurological disorders. However, the precise mechanisms underlying CNS immune surveillance remain elusive; particularly, the anatomical sites where peripheral adaptive immunity can sample CNS-derived Antigens and the cellular and molecular mediators orchestrating this surveillance. Here, we demonstrate that CNS-derived Antigens in the cerebrospinal fluid (CSF) accumulate around the dural sinuses, are captured by local antigen-presenting cells, and are presented to patrolling T cells. This surveillance is enabled by endothelial and mural cells forming the sinus stromal niche. T cell recognition of CSF-derived Antigens at this site promoted tissue resident phenotypes and effector functions within the dural meninges. These findings highlight the critical role of dural sinuses as a neuroimmune interface, where brain Antigens are surveyed under steady-state conditions, and shed light on age-related dysfunction and neuroinflammatory attack in animal models of Multiple Sclerosis.

Keywords
CNS autoimmunity; CSF flow; antigen presentation; dura mater; meningeal immunity; meningeal lymphatics; meninges; neuroimmunology; sinus; stromal cells.