Trends in Immunology
Volume 33, Issue 12, December 2012, Pages 579-589
Journal home page for Trends in Immunology

Review
Feature Review
Capture, crawl, cross: the T cell code to breach the blood–brain barriers

https://doi.org/10.1016/j.it.2012.07.004Get rights and content

The central nervous system (CNS) is an immunologically privileged site to which access of circulating immune cells is tightly controlled by the endothelial blood–brain barrier (BBB; see Glossary) localized in CNS microvessels, and the epithelial blood–cerebrospinal fluid barrier (BCSFB) within the choroid plexus. As a result of the specialized structure of the CNS barriers, immune cell entry into the CNS parenchyma involves two differently regulated steps: migration of immune cells across the BBB or BCSFB into the cerebrospinal fluid (CSF)-drained spaces of the CNS, followed by progression across the glia limitans into the CNS parenchyma. With a focus on multiple sclerosis (MS) and its animal models, this review summarizes the distinct molecular mechanisms required for immune cell migration across the different CNS barriers.

Section snippets

Immune privilege of the CNS

CNS homeostasis is the prerequisite for proper electrical activity of neural networks. The endothelial BBB in CNS parenchymal microvessels (Figure 1), the blood–leptomeningeal barrier (BLMB) in meningeal microvessels on the surface of the brain and spinal cord, as well as the epithelial BCSFB in the choroid plexus, protect the CNS from the constantly changing milieu in the blood stream by strictly controlling the movement of molecules across their interfaces (Box 1). This protective barrier

Principles of the multistep extravasation of immune cells

The recruitment of circulating immune cells into any given tissue is mediated by the sequential interaction of different adhesion and/or signaling molecules on immune cells and endothelial cells lining the vessel wall (summarized in 6, 7). The multistep interaction starts with an initial transient contact of the circulating immune cell with the vascular endothelium, mediated by adhesion molecules of the selectin family (L-, E-, or P-selectin) and their respective glycosylated ligands [e.g.,

Towards understanding immunosurveillance of the CNS

Immunosurveillance of the CNS requires the migration of circulating immune cells either across the endothelial BBB or BLMB or across the epithelial BCSFB in the absence of neuroinflammation. By tracing intravenously injected radioactively labeled encephalitogenic T cells in Lewis rats, it was first observed in the 1980s that freshly activated T cell blasts, but not resting T cells, can cross the BBB in the spinal cord 9, 10. Underlining the unique barrier characteristics of the BBB, however, T

Breaching the inflamed brain barriers

APCs are strategically localized behind the BBB, the BLMB, and the BCSFB. Perivascular spaces behind the BBB harbor rare dendritic cells (DCs) [30], whereas the leptomeningeal spaces harbor a significant number of leptomeningeal macrophages [3]. Finally, MHC class II-expressing macrophages referred to as Kolmer or epiplexus cells adhere to the apical aspect of the epithelial cells forming the BCSFB [31]. The CSF produced by the choroid plexus drains from the ventricles towards the

Transcellular versus paracellular diapedesis

Although endothelial ICAM-1 and ICAM-2 are essential for T cell crawling on the endothelium, passage of low numbers of T cells across brain endothelial monolayers can still be observed in the absence of ICAM-1 and ICAM-2 [54], suggesting different options for T cell diapedesis across the endothelial brain barriers. In principle, T cells can choose two alternative pathways to cross endothelial barriers. Extravasation of immune cells across vascular beds in peripheral tissues usually occurs

Breaching the endothelial basement membrane and the glia limitans

Upon penetration of the BBB or BLMB, T cells face the endothelial basement membrane where T cells preferentially migrate at sites containing the laminin isoform α4 but little or no laminin α5 in an α6β1-integrin-dependent manner 66, 67 (Figure 5). Mice lacking α4-laminin are less susceptible to EAE due to the inhibitory role of laminin α5 on T cell migration across endothelial cell basement membranes of the BBB and BLMB [66]. Thus, the observation that β1-integrins are essential for T cell

Concluding remarks

Here, we discussed how evolutionary selection pressure towards allowing immunosurveillance of the CNS without endangering its homeostasis might have led to the development of a two-walled compartment around the CNS. The outer wall, constituted by the BBB, BLMB or BCSFB can be breached by distinct T cell subsets. Specific signals released from the highly specialized outer barrier cells ensure that patrolling T cells remain in the CSF-drained perivascular or leptomeningeal compartments right

Acknowledgments

We thank Urban Deutsch for his critical comments on this review. The BE laboratory has been supported by the Microscopy Imaging Center of the University of Bern (www.mic.unibe.ch), the Swiss National Science Foundation, the Swiss Multiple Sclerosis Society, and the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreements n°201024 and n°202213 (European Stroke Network) and n°241861 (JUSTBRAIN). The RMR laboratory has been supported by the NIH (RO1NS32151; R21NS78420;

Glossary

Astrocytes
a subtype of ectodermal derived glial cells in the CNS characterized by many foot-like processes interacting with neurons and embracing the abluminal aspect of CNS microvessels.
Blood–brain barrier (BBB)
a diffusion barrier formed by the unique cellular and molecular characteristics of endothelial cells and the glia limitans perivascularis of the microvessels in the CNS parenchyma. At the level of CNS capillaries, the BBB forms a direct barrier.
Blood–cerebrospinal fluid barrier (BCSFB)
a

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