Trends in Immunology
The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms
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
References (99)
- et al.
Is the pial microvessel a good model for blood–brain barrier studies?
Brain Res. Brain Res. Rev.
(1997) Brain endothelium lack one of two pathways of P-selectin-mediated neutrophil adhesion
Blood
(1996)Nicotine induces leukocyte rolling and adhesion in the cerebral microcirculation of the mouse
J. Neuroimmunol.
(1997)Cellular immune reactivity within the CNS
Trends Neurosci.
(1986)Leukocyte traffic in the central nervous system: the participants and their roles
Semin. Immunol.
(1999)Lymphocyte trafficking and regional immunity
Adv. Immunol.
(1999)Requirements for passage of T lymphocytes across non-inflamed retinal microvessels
J. Neuroimmunol.
(2003)E- and P-selectin are not involved in the recruitment of inflammatory cells across the blood–brain barrier in experimental autoimmune encephalomyelitis
Blood
(1997)Comparison of ventricular and lumbar cerebrospinal fluid T cells in non-inflammatory neurological disorder (NIND) patients
J. Neuroimmunol.
(2005)Adhesion molecule phenotype of T lymphocytes in inflamed CNS
J. Neuroimmunol.
(1998)
Migratory activity and functional changes of green fluorescent effector cells before and during experimental autoimmune encephalomyelitis
Immunity
CD8+ T cells from patients with acute multiple sclerosis display selective increase of adhesiveness in brain venules: a critical role for P-selectin glycoprotein ligand-1
Blood
CD62L is required on effector cells for local interactions in the CNS to cause myelin damage in experimental allergic encephalomyelitis
Immunity
A monoclonal antibody to α4 integrin suppresses and reverses active experimental allergic encephalomyelitis
J. Neuroimmunol.
Interaction of α4-integrin with VCAM-1 is involved in adhesion of encephalitogenic T cell blasts to brain endothelium but not in their transendothelial migration in vitro
J. Neuroimmunol.
β7 Integrins contribute to demyelinating disease of the central nervous system
J. Neuroimmunol.
Anti-adhesion molecule therapy in experimental autoimmune encephalomyelitis
J. Neuroimmunol.
ICAM-1-dependent pathway is not critically involved in the inflammatory process of autoimmune encephalomyelitis or in cytokine-induced inflammation of the central nervous system
J. Neuroimmunol.
Leukocyte–endothelial adhesion molecules
Blood
T cell interaction with ICAM-1/ICAM-2-double-deficient brain endothelium in vitro: the cytoplasmic tail of endothelial ICAM-1 is necessary for transendothelial migration of T cells
Blood
Mouse CD99 participates in T-cell recruitment into inflamed skin
Blood
Intracerebral recruitment and maturation of dendritic cells in the onset and progression of experimental autoimmune encephalomyelitis
Am. J. Pathol.
Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity
Cell
Lymphocyte trafficking and regional immunity
Adv. Immunol.
Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm
Cell
Immunity to homologous grafted skin. III. The fate of skin homografts transplanted to the brain, to subcutaneous tissue and to anterior chamber of the eye
Br. J. Exp. Pathol.
Central nervous system endothelial cell–polymorphonuclear cell interactions during autoimmune demyelination
Am. J. Pathol.
IFN-γ shapes immune invasion of the central nervous system via regulation of chemokines
J. Immunol.
Rat and human myelin oligodendrocyte glycoproteins induce experimental autoimmune encephalomyelitis by different mechanisms in C57BL/6 mice
J. Immunol.
Tight junctions of the blood–brain barrier
Cell. Mol. Neurobiol.
Blood–brain–cerebrospinal fluid barriers
Migration of hematogenous cells through the blood–brain barrier and the initiation of CNS inflammation
Brain Pathol.
Homing to central nervous system vasculature by antigen-specific lymphocytes. I. Localization of 14C-labeled cells during acute, chronic, and relapsing experimental allergic encephalomyelitis
Lab. Invest.
Differential adhesion molecule requirements for immune surveillance and inflammatory recruitment
Brain
Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric G(i)-linked receptors
J. Immunol.
α4-Integrin–VCAM-1 binding mediates G protein-independent capture of encephalitogenic T cell blasts to CNS white matter microvessels
J. Clin. Invest.
Encephalitogenic T cells use LFA-1 during transendothelial migration but not during capture and adhesion in spinal cord microvessels in vivo
Eur. J. Immunol.
ICAM-1, VCAM-1, and MAdCAM-1 are expressed on choroid plexus epithelium but not endothelium and mediate binding of lymphocytes in vitro
Am. J. Pathol.
Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin
Proc. Natl. Acad. Sci. U. S. A.
Role of α4-integrins in lymphocyte homing to mucosal tissues in vivo
J. Immunol.
The development of experimental autoimmune encephalomyelitis in the mouse requires α4-integrin but not α4β7-integrin
J. Clin. Invest.
Distribution and phenotype of dendritic cells and resident tissue macrophages in the dura mater, leptomeninges, and choroid plexus of the rat brain as demonstrated in wholemount preparations
J. Comp. Neurol.
Lymphocyte targeting of the central nervous system: a review of afferent and efferent CNS-immune pathways
Brain Pathol.
Direct demonstration of the infiltration of murine central nervous system by Pgp-1/CD44high CD45RBlow CD4+ T cells that induce experimental allergic encephalomyelitis
J. Neuroimmunol.
Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis
Nat. Med.
Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis
Nat. Med.
Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo
Science
Lymphocytes infiltrating the CNS during inflammation display a distinctive phenotype and bind to VCAM-1 but not to MAdCAM-1
Int. Immunol.
Overlapping roles of P-selectin and α4 integrin to recruit leukocytes to the central nervous system in experimental autoimmune encephalomyelitis
J. Immunol.
Cited by (523)
Traumatic Brain Injury: A Comprehensive Review of Biomechanics and Molecular Pathophysiology
2024, World NeurosurgeryT cell infiltration mediates neurodegeneration and cognitive decline in Alzheimer's disease
2024, Neurobiology of DiseaseBlood and CSF findings of cellular immunity in anti-NMDAR encephalitis
2024, International ImmunopharmacologyRegulatory T cells: A suppressor arm in post-stroke immune homeostasis
2023, Neurobiology of DiseaseNeuroimmune interactions: From bench to bedside
2023, Translational Neuroimmunology: Neuroinflammation: Volume 7Understanding immune microenvironment alterations in the brain to improve the diagnosis and treatment of diverse brain diseases
2024, Cell Communication and Signaling