Trends in Immunology
Volume 26, Issue 9, September 2005, Pages 485-495
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The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms

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This review addresses current knowledge of the molecular trafficking signals involved in the migration of circulating leukocytes across the highly specialized blood–central nervous system (CNS) barriers during immunosurveillance and inflammation. In this regard, adhesion molecules and activating and chemotactic factors are also discussed and the regional variability in the brain and spinal cord parenchyma are also considered. Furthermore, direct passage into cerebrospinal fluid (CSF) is discussed, in the context of CNS immunosurveillance. The potential differences that characterize leukocyte entry into these varied anatomical sites are highlighted, with special emphasis on studies of the pathogenesis of multiple sclerosis and its animal models. An update on findings from clinical trials of natalizumab is also provided.

Section snippets

Introduction and background

Central nervous system (CNS) homeostasis is crucial for the proper function of neuronal cells. The seminal observation of Sir Peter Medawar, that the brain does not reject foreign tissue grafts [1], was followed by complementary findings: the CNS is devoid of classical antigen-presenting cells (APCs), such as dendritic cells (DCs); the CNS lacks constitutive MHC I and II expression on parenchymal cells; lymphatic vessels are not present in the CNS. Together, these data led to the conception

Anatomical routes for circulating leukocytes to cross blood–CNS barriers

The endothelial BBB has been considered the most obvious point of entry for circulating immune cells into the CNS (Figure 1). The term BBB originally described the lack of passive diffusion of molecules across the CNS capillaries. The BBB is formed by highly specialized endothelial cells, which inhibit transcellular molecular traffic owing to low pinocytotic activity, and restrict paracellular diffusion of hydrophilic molecules because of an elaborate network of complex interendothelial tight

Trafficking of T lymphocytes through the non-inflamed CNS and routine immunosurveillance

CNS inflammatory reactions (both pathologically and in the service of host defence) implicate mechanisms for immunosurveillance. Physiological trafficking of lymphocytes through the CNS supports the essential function of immunosurveillance; however, the study of lymphocyte entry into the non-inflamed CNS has not provided unambiguous results, probably owing to variation in the experimental approach.

Immigration of T lymphocytes across the blood-CNS barriers during inflammation: molecular mechanisms

In inflammatory conditions of the CNS, the expression of adhesion molecules and chemokines is induced on BBB endothelium and the choroid plexus epithelium, providing additional traffic signals for circulating leukocytes (Box 1). Thus, a significant number of leukocytes enter the CNS, making this process easier to investigate. Interestingly, even when the endothelial BBB becomes leaky, T-lymphocyte recruitment into the CNS remains tightly controlled because parenchymal lymphocytes comprise a

Tethering and rolling of leukocytes on inflamed BBB endothelium

During EAE, or following intravenous TNF-α, tethering and rolling of blood leukocytes can be observed readily in superficial brain and meningeal microvessels by performing IVM using a cranial window [35] or through the intact skulls of young mice [36]. In inflamed murine vessels, CD8+ T lymphocytes from MS patients preferentially roll via P-selectin glycoprotein ligand-1 (PSGL-1), whereas CD4+ T lymphocytes roll via α4-integrin [36]. By contrast, PSGL-1–E- or P-selectin interactions are

Activation step

Integrin activation, mediated by signalling through G-protein-coupled receptors, is essential for leukocyte arrest under flow conditions. Chemokines and their receptors are the largest family of molecules that deliver such signals and they also orchestrate temporo-spatial cellular localization in developmental organ patterning and immunity. IVM studies of T-lymphocyte interactions with the superficial brain and spinal cord microvasculature demonstrate that G-protein signalling is required for

Firm adhesion and diapedesis

In several studies, the adhesion molecules ICAM-1 and VCAM-1 were upregulated on CNS microvascular endothelial cells during EAE 12, 53, 54. The expression of VCAM by human cerebral vasculature remains controversial, with one positive study [55] but two studies showing VCAM on activated microglia but not on endothelium 22, 56. With one exception [57], MAdCAM-1 (mucosal addressin cell adhesion molecule-1) expression has not been detected at the BBB during EAE [53]. Perivascular inflammatory cells

Does the BBB prompt transcellular leukocyte migration?

During diapedesis across the inflamed BBB, leukocytes migrate by a transcellular pathway through endothelial cells, leaving tight junctions intact (reviewed in Ref. [76]). Transcellular migration of leukocytes might be considered a specialization of the nervous system endothelial cells that are connected by complex tight junctions. Recent in vitro studies confirmed transendothelial leukocyte migration involving LFA-1 and ICAM-1 [77].

It remains pertinent to address the involvement of junctional

The choroid plexus during CNS inflammation

ICAM-1 and VCAM-1 were detected previously on inflamed choroid plexus epithelium (CPE) 84, 85. These molecules mediate inflammatory cell binding to CPE in Stamper-Woodruff assays [21]. Both IHC and in situ hybridization demonstrated upregulation of VCAM-1 and ICAM-1 and de novo expression of MAdCAM-1 in the choroid plexus during EAE. Ultrastructural studies localized ICAM-1, VCAM-1 and MAdCAM-1 to the apical surface of CPE cells and their absence on the fenestrated endothelial cells within the

New developments

EAE studies summarized earlier conclude that α4–integrin has a central role in leukocyte migration across the blood–tissue barriers of the CNS. Clinical MS trials confirm this hypothesis: natalizumab (humanized anti-α4 integrin antibodies) has produced the most impressive reduction of MS inflammatory disease activity (relapses; inflammatory gadolinium-enhancing lesions or new T2-bright magnetic resonance imaging lesions) yet reported [91] and was rapidly approved for use in patients.

Conclusions, implications and complications

Immune cells patrol the CNS to perform immunosurveillance. However, for this purpose they migrate in various ways to different destinations. Lymphoblasts cross the endothelial inflamed BBB to ‘meet’ APCs, such as perivascular DCs of the CNS parenchyma [31]. Without antigen-triggered activation these cells will not persist, nor traverse the glia limitans into the CNS parenchyma. Such invasion only occurs under pathological conditions, during which ‘traffic signals’ are altered on the BBB

Update

The New England Journal of Medicine recently carried case reports of all three confirmed PML patients from natalizumab clinical trials 95, 96, 97. These reports were supplemented with two editorials, one humbly acknowledging the courage of patients that enter clinical trials [98]; the other editorial [99] proposed an hypothesis: that PML occurs in natalizumab recipients because of deficient immunosurveillance at sites of latent infection and, possibly, the CNS as well. However, the case

Acknowledgements

The B.E. laboratory has been supported by Astra Zeneca, the German Research Foundation (SFB 293, SFB 629), the German Ministry for Education and Research, the Swiss National Science Foundation (3100A0–104096), GlaxoSmithKline and the Swiss Multiple Sclerosis Society. The R.M.R. laboratory has been supported by the US NIH (NS32151; NS38667; NS36674; TW6012), the Charles A. Dana Foundation, the Nancy Davis Center Without Walls and with fellowship and pilot project awards from the National

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