TY - JOUR
T1 - Functional characterization of the dural sinuses as a neuroimmune interface
AU - Rustenhoven, Justin
AU - Drieu, Antoine
AU - Mamuladze, Tornike
AU - de Lima, Kalil Alves
AU - Dykstra, Taitea
AU - Wall, Morgan
AU - Papadopoulos, Zachary
AU - Kanamori, Mitsuhiro
AU - Salvador, Andrea Francesca
AU - Baker, Wendy
AU - Lemieux, Mackenzie
AU - Da Mesquita, Sandro
AU - Cugurra, Andrea
AU - Fitzpatrick, James
AU - Sviben, Sanja
AU - Kossina, Ross
AU - Bayguinov, Peter
AU - Townsend, Reid R.
AU - Zhang, Qiang
AU - Erdmann-Gilmore, Petra
AU - Smirnov, Igor
AU - Lopes, Maria Beatriz
AU - Herz, Jasmin
AU - Kipnis, Jonathan
N1 - Funding Information:
We would like to thank S. Smith for editing the manuscript, A. Impagliazzo for the graphical abstract design, J. Sokolowski for help with the human sample collection, S. Blackburn, N. Al-Hamadani, X. Wang, and E. Griffin for animal care, and S. Brophy for lab management. We thank all the members of the Kipnis lab for their valuable comments during multiple discussions of this work. We thank the University of Virginia Flow Cytometry Core and Washington University in St. Louis Department of Pathology and Immunology Flow Cytometry and Fluorescence Activated Cell Sorting Core for help with cell sorting. We thank the University of Virginia Genome Analysis and Technology Core and the Washington University in St. Louis McDonnel Genome Institute (MGI) for help with single-cell RNA-seq library preparation and sequencing. We thank the Washington University Center for Cellular Imaging (WUCCI), which is funded in part by The Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital ( CDI-CORE-2015-505 and CDI-CORE-2019-813 ) and the Foundation for Barnes-Jewish Hospital ( 3770 and 4642 ) for assistance with intravital microscopy and electron microscopy sample preparation and imaging. We thank the Washington University Proteomics Shared Resource (WU-PSR) for help with proteomics experiments, particularly Yiling Mi and Rose Connors for their expert technical assistance. The WU-PSR is supported in part by the WU Institute of Clinical and Translational Sciences ( NCATS UL1 TR000448 ), the Mass Spectrometry Research Resource ( NIGMS P41 GM103422 ), and the Siteman Comprehensive Cancer Center Support Grant ( NCI P30 CA091842 ). This work was supported by grants (to J.K.) from the NIH/NIA ( AG034113 , AG057496 , and AT010416 ) and the BEE Consortium from Cure Alzheimer’s Fund .
Funding Information:
We would like to thank S. Smith for editing the manuscript, A. Impagliazzo for the graphical abstract design, J. Sokolowski for help with the human sample collection, S. Blackburn, N. Al-Hamadani, X. Wang, and E. Griffin for animal care, and S. Brophy for lab management. We thank all the members of the Kipnis lab for their valuable comments during multiple discussions of this work. We thank the University of Virginia Flow Cytometry Core and Washington University in St. Louis Department of Pathology and Immunology Flow Cytometry and Fluorescence Activated Cell Sorting Core for help with cell sorting. We thank the University of Virginia Genome Analysis and Technology Core and the Washington University in St. Louis McDonnel Genome Institute (MGI) for help with single-cell RNA-seq library preparation and sequencing. We thank the Washington University Center for Cellular Imaging (WUCCI), which is funded in part by The Children's Discovery Institute of Washington University and St. Louis Children's Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813) and the Foundation for Barnes-Jewish Hospital (3770 and 4642) for assistance with intravital microscopy and electron microscopy sample preparation and imaging. We thank the Washington University Proteomics Shared Resource (WU-PSR) for help with proteomics experiments, particularly Yiling Mi and Rose Connors for their expert technical assistance. The WU-PSR is supported in part by the WU Institute of Clinical and Translational Sciences (NCATS UL1 TR000448), the Mass Spectrometry Research Resource (NIGMS P41 GM103422), and the Siteman Comprehensive Cancer Center Support Grant (NCI P30 CA091842). This work was supported by grants (to J.K.) from the NIH/NIA (AG034113, AG057496, and AT010416) and the BEE Consortium from Cure Alzheimer's Fund. Conceptualization, J.R. A.D. T.M. K.A.d.L. J.H. and J.K.; methodology, J.R. A.D. T.M. K.A.d.L. Z.P. M.K. A.F.S. J.F. S.S. R.K. P.B. R.R.T. Q.Z. P.E-.G. I.S. J.H. and J.K.; formal analysis, J.R. T.D. M.W. Z.P. R.R.T. Q.Z. and J.H.; investigation, J.R. A.D. T.M. K.A.d.L. Z.P. M.K. A.F.S. W.B. M.L. S.D.M. A.C. S.S. R.K. P.B. Q.Z. P.E.-G. I.S. and J.H.; resources, J.F. S.S. R.K. P.B. R.R.T. Q.Z. P.E.-G. and M.-B.L.; data curation, T.D. M.W. R.R.T. and Q.Z.; writing – original draft, J.R. and J.K.; writing – review & editing, J.R. and J.K.; visualization, J.R.; supervision, J.K.; funding acquisition, J.K. J.K. is a shareholder and a member of the scientific advisory group for PureTech.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/2/18
Y1 - 2021/2/18
N2 - 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.
AB - 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.
KW - CNS autoimmunity
KW - CSF flow
KW - antigen presentation
KW - dura mater
KW - meningeal immunity
KW - meningeal lymphatics
KW - meninges
KW - neuroimmunology
KW - sinus
KW - stromal cells
UR - http://www.scopus.com/inward/record.url?scp=85100636148&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2020.12.040
DO - 10.1016/j.cell.2020.12.040
M3 - Article
C2 - 33508229
AN - SCOPUS:85100636148
SN - 0092-8674
VL - 184
SP - 1000-1016.e27
JO - Cell
JF - Cell
IS - 4
ER -