Molecular mechanisms involved in T cell migration across the blood–brain barrier
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In the healthy individuum lymphocyte traffic into the central nervous system (CNS) is very low and tightly controlled by the highly specialized blood–brain barrier (BBB). In contrast, under inflammatory conditions of the CNS such as in multiple sclerosis or in its animal model experimental autoimmune encephalomyelitis (EAE) circulating lymphocytes and monocytes/macrophages readily cross the BBB and gain access to the CNS leading to edema, inflammation and demyelination. Interaction of circulating leukocytes with the endothelium of the blood–spinal cord and blood–brain barrier therefore is a critical step in the pathogenesis of inflammatory diseases of the CNS. Leukocyte/endothelial interactions are mediated by adhesion molecules and chemokines and their respective chemokine receptors. We have developed a novel spinal cord window preparation, which enables us to directly visualize CNS white matter microcirculation by intravital fluorescence videomicroscopy. Applying this technique of intravital fluorescence videomicroscopy we could provide direct in vivo evidence that encephalitogenic T cell blasts interact with the spinal cord white matter microvasculature without rolling and that α4-integrin mediates the G-protein independent capture and subsequently the G-protein dependent adhesion strengthening of T cell blasts to microvascular VCAM-1. LFA-1 was found to neither mediate the G-protein independent capture nor the G- protein dependent initial adhesion strengthening of encephalitogenic T cell blasts within spinal cord microvessel, but was rather involved in T cell extravasation across the vascular wall into the spinal cord parenchyme. Our observation that G-protein mediated signalling is required to promote adhesion strengthening of encephalitogenic T cells on BBB endothelium in vivo suggested the involvement of chemokines in this process. We found functional expression of the lymphoid chemokines CCL19/ELC and CCL21/SLC in CNS venules surrounded by inflammatory cells in brain and spinal cord sections of mice afflicted with EAE suggesting that the lymphoid chemokines CCL19 and CCL21 besides regulating lymphocyte homing to secondary lymphoid tissue might be involved in T lymphocyte migration into the immuneprivileged CNS during immunosurveillance and chronic inflammation. Here, I summarize our current knowledge on the sequence of traffic signals involved in T lymphocyte recruitment across the healthy and inflamed blood–brain and blood–spinal cord barrier based on our in vitro and in vivo investigations.
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- Alt, C, Laschinger, M, Engelhardt, B 2002Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL21 (SLC) at the blood–brain barrier suggests their possible involvement in lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis.Eur J Immunol3221332144CrossRefPubMedGoogle Scholar
- Engelhardt, B, Laschinger, M, Schulz, M, Samulowitz, U, Vestweber, D, Hoch, G 1998aThe development of experimental autoimmune encephalomyelitis in the mouse requires alpha4-integrin but not alpha4beta7-integrin.J Clin Invest10220962105Google Scholar
- Engelhardt B, Laschinger M, Vajkoczy P (2004) Molecular mechanisms involved in lymphocyte interaction with blood–spinal cord barrier endothelium in vivo. In: Sharma HS, Westman J (eds) The blood–spinal cord and brain barriers in health and disease. Elsevier Academic Press, pp 19–31Google Scholar
- Piccio, L, Rossi, B, Scarpini, E, Laudanna, C, Giagulli, C, Issekutz, AC, Vestweber, D, Butcher, EC, Constantin, G 2002Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric G(i)-linked receptors.J Immunol16819401949PubMedGoogle Scholar
- Vajkoczy, P, Ullrich, A, Menger, MD 2000Intravital fluorescence videomicroscopy to study tumor angiogenesis and microcirculation.Neoplasia (New York)25361Google Scholar
- Wekerle, H, Linington, C, Lassmann, H, Meyermann, R 1986Cellular immune reactivity within the CNS.TINS9271277Google Scholar
- Wolburg, H, Wolburg-Buchholz, K, Kraus, J, Rascher-Eggstein, G, Liebner, S, Hamm, S, Duffner, F, Grote, EH, Risau, W, Engelhardt, B 2003Localization of claudin-3 in tight junctions of the blood–brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme.Acta Neuropathol105586592PubMedGoogle Scholar