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  • Review Article
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Three or more routes for leukocyte migration into the central nervous system

Key Points

  • The central nervous system (CNS) has been characterized as an immunologically privileged site in the past, but it should more accurately be viewed as immunologically specialized.

  • It is probable that control of immune reactivity to components of the CNS cannot occur solely by sequestering neuroantigens behind the blood–brain barrier (BBB). Rather, trafficking of immunocompetent cells into the CNS must also be tightly regulated.

  • The CNS is protected, nourished and supported by a unique and diverse combination of vascular elements and by the cerebrospinal fluid (CSF). Consequently, mechanisms for recruitment of leukocytes across different vascular beds and into varied fluid compartments of the CNS will differ.

  • Despite the successful studies of T-cell homing to lymphoid organs, small intestines and skin, organ-selective trafficking determinants for the CNS have not been identified.

  • It is possible to define three distinct routes for leukocytes entry into the CNS: from blood to CSF across the choroid plexus; from blood to the subarachnoid space through meningeal vessels; and from blood to parenchymal perivascular spaces.

  • Adoptive transfer of primed encephalitogenic T cells leads to the accumulation of a small number of cells in the meninges, the choroid plexus and, perhaps, the parenchyma within two hours after transfer.

  • This low-efficiency first wave of cell migration might function to activate parenchymal vessels for interaction with the subsequent large-scale entry of leukocytes, as recent studies using intravital microscopy indicate that non-activated parenchymal vessels are refractory to communication with lymphocytes.

Abstract

Leukocyte migration into and through tissues is fundamental to normal physiology, immunopathology and host defence. Leukocyte entry into the central nervous system (CNS) is restricted, in part, because of the blood–brain barrier (BBB). During the past decade, crucial components that are involved in the process of leukocyte migration have been identified and progress has been made in understanding the mechanisms of neuroinflammatory reactions. In this review, present knowledge of the trafficking determinants that guide the migration of leukocytes is superimposed onto the vascular and compartmental anatomy of the CNS. We discuss three distinct routes for leukocytes to enter the CNS and consider how different populations of leukocytes use trafficking signals to gain entry.

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Figure 1: Anatomical structures involved in the arterial supply of the CNS and the cerebrospinal fluid circulation.
Figure 2: Afferent and efferent mechanisms of immune surveillance in the CNS.
Figure 3: A multi-step model for leukocyte entry into the cerebrospinal fluid (CSF).

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Acknowledgements

The authors would like to thank S. M. Staugaitis and J. J. Campbell for an insightful critique of this paper. We also acknowledge J. Teale, A. Cardona and A. Luster for communicating results before publication. Research in Dr. Ransohoff's laboratory is supported by the National Institutes of Health.

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DATABASES

LocusLink

CCL21

CCR1

CCR2

CCR3

CCR5

CCR6

CCR7

CD4

CD8

CD44

CXCL10

CXCR2

CXCR3

CXCR4

ICAM1

MBP

OX40

PECAM

P-selectin

PSGL1

TNF

VCAM1

VLA4

OMIM

Alzheimer disease

multiple sclerosis

FURTHER INFORMATION

Workshop on choroid plexus

G-protein-coupled receptors datatbase

Chemokine database

Glossary

BLOOD-BRAIN BARRIER (BBB).

The physiological barrier that separates blood from brain parenchyma. It consists of endothelial cells with tight junctions that are surrounded by a continuous basement membrane and astroglial end-feet.

MICROGLIA

Interstitial cells of mesodermal origin that form part of the supporting structure of the central nervous system. They have a migratory capacity and function as phagocytes of the nervous tissue.

ASTROGLIA

Star-shaped cells of ectodermal origin that provide nutrients, support and insulation for neurons.

SUBARACHNOID SPACE

A space between the arachnoid and pial membranes that surround the brain and spinal cord that is filled with cerebrospinal fluid. It contains fibrous trabeculae, blood vessels and antigen-presenting cells.

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE).

An animal model that mimics some of the clinical and histopathological characteristics of multiple sclerosis. EAE can be induced in various species by immunization with myelin antigens or adoptive transfer of neuroantigen-specific T cells.

TIGHT JUNCTIONS

Intercellular junctions where adjacent plasma membranes are joined tightly together, occluding the intercellular space and limiting the intercellular passage of molecules.

VIRCHOW–ROBIN SPACE

A space that surrounds blood vessels for a short distance as they enter the brain from the cortical surface, defined by extensions of the arachnoid and pial membranes.

MICROVILLI

Small processes or protrusions from the cell surface that increase the surface size of the cell.

CENTRAL MEMORY T CELLS

Previously activated memory T cells that have encountered antigen in secondary lymphoid organs and obtained the capacity to migrate through extralymphoid tissues, but retain receptors and ligands, such as CC-chemokine receptor 7 and L-selectin, allowing the cells to return to the lymphoid compartment.

T HELPER 1/2 CELLS (TH1/TH2).

Activated CD4+ T cells differentiate into two distinct phenotypes that are associated with highly polarized immune responses. Generally, TH1 cells produce high levels of interferon-γ, lymphotoxin and tumour-necrosis factor, and are associated with cell-mediated immunity, whereas TH2 cells produce high levels of interleukin-4 (IL-4), IL-5 and IL-13, and are associated with humoral immunity.

TOLL-LIKE RECEPTORS (TLRs).

A family of receptors that recognize conserved products that are unique to microorganisms, such as lipopolysaccharide. Stimulation through TLRs induces maturation and activation of dendritic cells, leading to optimal activation of the adaptive immune response.

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Ransohoff, R., Kivisäkk, P. & Kidd, G. Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 3, 569–581 (2003). https://doi.org/10.1038/nri1130

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