Immunosurveillance of the CNS Immune Cell Entry into the Healthy CNS

Direct evidence for immune cell entry into the healthy CNS was established by studying experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, reviewed by (Lassmann 1983; Martin and Mc-Farland 1995; Sospedra and Martin 2005). In contrast to multiple sclerosis, the etiology of which remains unknown to date, EAE is a T cell mediated autoimmune disease of the CNS that can be induced in susceptible animals including different rat and mouse strains by immunization with selected myelin components, reviewed in (Wekerle et al. 1994) or by intravenous injection of freshly activated neuroantigen-specific, i.e., encephalitogenic, CD4+ T cell blasts into syngeneic naive recipients (Ben-Nun et al. 1981). In both types of EAE, activation of the CD4+ auto-aggressive T cells takes place outside of the CNS. Tracing intravenously injected radioactively labelled encephalitogenic T cell blasts revealed that they are able to penetrate the non-inflamed BBB in healthy Lewis rats (Hickey 1991; Wekerle et al. 1986). It was also established that a high activation state rather than neuroantigen-specificity of the CD4+ T lymphoblasts was required for crossing the BBB as resting T cells irrespective of their antigen-specificity failed to penetrate the BBB in this model (Hickey 1991; Wekerle et al. 1986). In these original studies, radioac-tively labeled T cells were detected in perivascular locations within the brain parenchyma at the earliest 6 h after their peripheral injection. By observing the migration of the fluorescently labeled encephalitogenic T cell blast into the CNS it was established more recently that 2 h after peripheral injection into mice, T cells can only be observed within the meninges and the choroid plexus parenchyma (Carrithers et al. 2000). Interestingly, the latter study established a role for P-selectin in T cell recruitment into the meningeal and choroid plexus sites. As P-selectin is not stored in the Weibel-Palade bodies of the CNS parenchymal vessels (Mayadas et al. 1993), but minute amounts of constitutive P-selectin are detectable within the CNS (Kerfoot and Kubes 2002), it is tempting to speculate that the restricted expression of P-selectin in endothelial cells of meningeal and choroid plexus microves-sels determines different kinetics of T cell entry into selected sites within the CNS. However, intravital epifluorescence video microscopy (IVM) studies of the superficial brain microcirculation failed to detect any interaction of en-cephalitogenic T cell blasts with healthy CNS microvessels (Piccio et al. 2002). Taken together, these observations suggest that IVM of the brain might fail to detect the rare T cell encounters with CNS microvessels in the healthy animal as observed by the in vivo homing studies performed by Carrithers and colleagues.

In contrast, IVM studies of the non-inflamed spinal cord white matter demonstrated the interaction of encephalitogenic T lymphoblasts with the microvasculature at this site, which at the same time was found to be unique (Vajkoczy et al. 2001). T cells were found to interact with spinal cord capillaries and post-capillary venules. Within the post-capillary venules, T cell-BBB interaction was found to be uniquely characterized by a complete lack of T cell rolling and the predominant involvement of a4-integrin and its endothelial ligand VCAM-1 in both, the initial T cell capture and the subsequent G-protein dependent adhesion strengthening to the spinal cord white matter microvascular wall (Vajkoczy et al. 2001). The inte-grin LFA-1 (Leukocyte function associated antigen 1, [email protected], CD11aCD18) was found to support the migration of T lymphoblasts across the non-inflamed spinal cord white matter microvascular wall and completed dia-pedesis was first observed 3 h post-injection (Laschinger et al. 2002; Vajkoczy et al. 2001).

These observations suggest that in the healthy CNS, immune cell-endothelial cell encounters within the CNS microvessels are few and that there seem to be differences in the interactions at the vascular wall between meningeal versus parenchymal CNS sites. Molecular and cellular differences for the meningeal and parenchymal microvascular beds have been described (Allt and Lawrenson 1997; Rascher and Wolburg 1997), i.e., meningeal mi-crovessels lack astrocytic ensheathment, conversely, parenchymal microves-

sels lack stored P-selectin (Barkalow et al. 1996; Engelhardt et al. 1997). Furthermore, tight junctions have been described between some endothelial cells of pial vessels, which differ from the complex P-face associated tight junctions found between endothelial cells in parenchymal microvessels, as they leave a discernible gap between adjacent endothelial cell membranes (Allt and Lawrenson 1997). Fenestrated microvessels within the choroid plexus are, strictly speaking, outside of the CNS. As P-selectin was shown to be involved in T cell entry into the meningeal sites and into the choroid plexus during immunosurveillance (Carrithers et al. 2000), it is tempting to speculate that different molecular mechanisms are operating to specifically guide immune cells to distinct CNS compartments. Without antigen-triggered activation, immune cells apparently do not persist behind the BBB and do not properly immigrate across the glia limitans into the CNS parenchyma (Flugel et al. 2001). Thus, immunosurveillance of the CNS is a critical component of host defence and seems without antigen-specific activation of the immune cells behind the BBB to be restricted to the perivascular CNS compartments and the choroid plexus.

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