Journal of Neural Transmission

, Volume 113, Issue 4, pp 477–485 | Cite as

Molecular mechanisms involved in T cell migration across the blood–brain barrier

  • B. Engelhardt
Article

Summary.

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.

Keywords: Blood–brain barrier, lymphocyte trafficking, adhesion molecule. 

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References

  1. 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
  2. Butcher, EC, Williams, M, Youngman, K, Rott, L, Briskin, M 1999Lymphocyte trafficking and regional immunity.Adv Immunol72209253PubMedGoogle Scholar
  3. 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
  4. 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
  5. Engelhardt, B, Martin-Simonet, MT, Rott, LS, Butcher, EC, Michie, SA 1998bAdhesion molecule phenotype of T lymphocytes in inflamed CNS.J Neuroimmunol8492104CrossRefGoogle Scholar
  6. Engelhardt, B, Vestweber, D, Hallmann, R, Schulz, M 1997E- and P-selectin are not involved in the recruitment of inflammatory cells across the blood–brain barrier in experimental autoimmune encephalomyelitis.Blood9044594472PubMedGoogle Scholar
  7. Engelhardt, B, Kempe, B, Merfeld-Clauss, S, Laschinger, M, Furie, B, Wild, MK, Vestweber, D 2005PSGL-1 is not required for the development of experimental autoimmune encephalomyelitis in SJL and C57B16 mice.J Immunol17512671275PubMedGoogle Scholar
  8. Hickey, WF, Hsu, BL, Kimura, H 1991T-lymphocyte entry into the central nervous system.J Neurosci Res28254260CrossRefPubMedGoogle Scholar
  9. Kerfoot, S, Kubes, P 2002Overlapping roles of P-selectin and alpha 4 integrin to recruit leukocytes to the central nervous system in experimental autoimmune encephalomyelitis.J Immunol16910001006PubMedGoogle Scholar
  10. Kleinschmidt-Demasters, BK, Tyler, KL 2005Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis.N Engl J Med353369374CrossRefPubMedGoogle Scholar
  11. Langer-Gould, A, Atlas, SW, Bollen, AW, Pelletier, D 2005Progressive multifocal leukoencephalopathy in a patient treated with natalizumab.N Engl J Med353375381CrossRefPubMedGoogle Scholar
  12. Laschinger, M, Engelhardt, B 2000Interaction of alpha4-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 Neuroimmunol1023243CrossRefPubMedGoogle Scholar
  13. Laschinger, M, Vajkoczy, P, Engelhardt, B 2002Encephalitogenic T cells use LFA-1 during transendothelial migration but not during capture and adhesion in spinal cord microvessels in vivo.Eur J Immunol3235983606CrossRefPubMedGoogle Scholar
  14. Lyck, R, Reiss, Y, Gerwin, N, Greenwood, J, Adamson, P, Engelhardt, B 2003T 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.Blood10236753683CrossRefPubMedGoogle Scholar
  15. Miller, DH, Khan, OA, Sheremata, WA, Blumhardt, LD, Rice, GP, Libonati, MA, Willmer-Hulme, AJ, Dalton, CM, Miszkiel, KA, O’Connor, PW 2003A controlled trial of natalizumab for relapsing multiple sclerosis.N Engl J Med3481523PubMedGoogle Scholar
  16. 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
  17. Steffen, BJ, Butcher, EC, Engelhardt, B 1994Evidence for involvement of ICAM-1 and VCAM-1 in lymphocyte interaction with endothelium in experimental autoimmune encephalomyelitis in the central nervous system in the SJL/J mouse.Am J Pathol145189201PubMedGoogle Scholar
  18. Vajkoczy, P, Laschinger, M, Engelhardt, E 2001Alpha4-integrin-VCAM-1 binding mediates G protein-independent capture of encephalitogenic T cell blasts to CNS white matter microvessels.J Clin Invest108557565CrossRefPubMedGoogle Scholar
  19. Vajkoczy, P, Ullrich, A, Menger, MD 2000Intravital fluorescence videomicroscopy to study tumor angiogenesis and microcirculation.Neoplasia (New York)25361Google Scholar
  20. Van Assche, G, Van Ranst, M, Sciot, R, Dubois, B, Vermeire, S, Noman, M, Verbeeck, J, Geboes, K, Robberecht, W, Rutgeerts, P 2005Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease.N Engl J Med353362368CrossRefPubMedGoogle Scholar
  21. Wekerle, H, Linington, C, Lassmann, H, Meyermann, R 1986Cellular immune reactivity within the CNS.TINS9271277Google Scholar
  22. 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
  23. Wolburg, H, Wolburg-Buchholz, K, Engelhardt, B 2005Diapedesis of mononuclear cells across cerebral venules during experimental autoimmune encephalomyelitis leaves tight junctions intact.Acta Neuropathol109181190CrossRefPubMedGoogle Scholar
  24. Xu, H, Manivannan, A, Liversidge, J, Sharp, PF, Forrester, JV, Crane, IJ 2003Requirements for passage of T lymphocytes across non-inflamed retinal microvessels.J Neuroimmunol1424757CrossRefPubMedGoogle Scholar
  25. Yednock, TA, Cannon, C, Fritz, LC, Sanchez Madrid, F, Steinman, L, Karin, N 1992Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin.Nature3566366CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag/Wien 2006

Authors and Affiliations

  • B. Engelhardt
    • 1
  1. 1.Theodor Kocher Institute, University of BernSwitzerland

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