Trends in Immunology
ReviewFeature ReviewCapture, crawl, cross: the T cell code to breach the blood–brain 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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