SCIENCE science.org 29 OCTOBER 2021 • VOL 374 ISSUE 6567 548-APHOTO: MIKE NICHOLS/MEDICAL PORTRAIT STUDIO
NEUROSCIENCEA privileged brain
Local neuroimmune collaboration safeguards
the central nervous system
By Justin RustenhovenO
ur immune system and central ner-
vous system (CNS) continuously
surveil the environment and make
on-demand adjustments to maintain
homeostasis. Yet despite their com-
monalities, these systems were origi-
nally believed to be entirely separate from
one another.
Unlike peripheral tissues, the CNS lacks
a parenchymal lymphatic network, and the
blood–brain barrier and blood–cerebrospi-
nal fluid (CSF) barrier restrict homeostatic
immune cell entrance ( 1 ). This knowledge
fueled a long-held dogma of CNS “immune
privilege,” which suggested an inability of the
brain and spinal cord to mount a
functional immune response to lo-
cal insults ( 2 , 3 ). But why would our
brain and spinal cord, arguably our
most complex and delicate organs,
lack such a fundamental arrange-
ment to detect dysfunction? We
posited the complex nature of the
CNS necessitates its own special-
ized immunological setup to detect and re-
spond to perturbations accordingly ( 4 ).SURVEILLING CNS BORDERS
The flushing of brain interstitial fluid into
the surrounding CSF revealed a potential
pathway facilitating CNS immune surveil-
lance ( 5 ). This clearance mechanism shut-
tles the soluble immunogenic constituents
of the brain, including microbial pathogens,
tumor neoantigens, and even self-antigens,
out of the CNS and enables access to periph-
eral tissues. We therefore reasoned that the
detection of these soluble antigens could
allow the immune system to continuously
probe for potential CNS dysfunction and
explored the locations and mechanisms me-
diating such monitoring.
Our research suggests that neuroimmune
surveillance is concentrated at the edges of
the CNS, in brain-border tissues called the
dural meninges ( 6 ). Instead of CSF flowing
into venous blood ( 7 ), our imaging revealed
CNS-derived antigens in the CSF rapidly
accumulated in the dural meninges of themouse, specifically surrounding large vas-
cular structures called the dural sinuses
( 6 ). Demonstrating evolutionary conserved
fluid dynamics, this pathway was also vi-
sualized by magnetic resonance imaging in
human patients ( 8 ), while liquid chroma-
tography–mass spectrometry revealed CNS-
enriched antigens surrounding human du-
ral sinuses ( 6 ). Critically, the dural sinuses
also contained highly organized hubs of
antigen-presenting cells capable of captur-
ing brain-derived antigens and presenting
them on their surface for recognition by
another specialized immune cell, the T cell.
All components necessary for CNS anti-
gen presentation are concentrated at the
dural sinuses, but can adaptive immune
cells surveil this tissue? We gen-
erated a single-cell RNA sequenc-
ing (scRNA-seq) meningeal atlas
and found that the dural sinuses
contain a stromal niche perfectly
primed for T cell extravasation
via specialized endothelium and
stromal-derived chemokines ( 6 ).
Using in vivo imaging and trans-
fer of antigen-specific T cells, we also con-
firmed that, unlike the CNS vasculature, T
cells constantly infiltrate this site and, upon
recognition of CSF-derived antigens, initi-
ate an effector response designed to restore
brain homeostasis.
These findings reshaped our understand-
ing of neuroimmune surveillance, high-
lighting the dural meninges as a critical site
for the recognition of CNS perturbations.
The question then became: What do the
meninges do with this information?BESPOKE IMMUNE CELLS FOR THE CNS
There is a large pool of bone marrow situ-
ated on the periphery of the brain, in the
skull overlying the dural sinuses. Here, active
hematopoiesis—the formation of new blood
cells—occurs via resident lymphoid and my-
eloid progenitors ( 9 ). In mice and humans,
this bone marrow niche is directly connected
to the underlying dura matter by way of ossi-
fied channels, providing direct and uninter-
rupted passage between the bone marrow of
the skull and the underlying dural meninges
( 10 , 11 ). Parabiotic pairing, skull transplanta-
tion models, and selective irradiation of dis-
crete bone marrow niches were used in mice
to demonstrate that these channels are con-Department of Pathology and Immunology, Washington
University in St. Louis, St. Louis, MO 63110, USA. Email:
[email protected]FINALIST
Justin
Rustenhoven
Justin Rusten-
hoven received
an undergraduate
degree and PhD in
pharmacology from the University
of Auckland in New Zealand. He per-
formed his postdoctoral training in
the laboratory of Professor Jonathan
Kipnis at Washington University
in St. Louis, where he continues
to work as a research fellow. His
research explores the mechanisms
underlying immune surveillance of
the central nervous system from the
brain’s borders.
science.org/doi/10.1126/science.abl7122PRIZE ESSAY
INSIGHTS