The blood–brain barrier (BBB) and the environment of the central nervous system (CNS) guard the nervous tissue from peripheral immune cells. In the autoimmune disease multiple sclerosis, myelin-reactive T-cell blasts are thought to transgress the BBB1,2 and create a pro-inflammatory environment in the CNS, thereby making possible a second autoimmune attack that starts from the leptomeningeal vessels and progresses into the parenchyma3,4,5,6. Using a Lewis rat model of experimental autoimmune encephalomyelitis, we show here that contrary to the expectations of this concept, T-cell blasts do not efficiently enter the CNS and are not required to prepare the BBB for immune-cell recruitment. Instead, intravenously transferred T-cell blasts gain the capacity to enter the CNS after residing transiently within the lung tissues. Inside the lung tissues, they move along and within the airways to bronchus-associated lymphoid tissues and lung-draining mediastinal lymph nodes before they enter the blood circulation from where they reach the CNS. Effector T cells transferred directly into the airways showed a similar migratory pattern and retained their full pathogenicity. On their way the T cells fundamentally reprogrammed their gene-expression profile, characterized by downregulation of their activation program and upregulation of cellular locomotion molecules together with chemokine and adhesion receptors. The adhesion receptors include ninjurin 1, which participates in T-cell intravascular crawling on cerebral blood vessels. We detected that the lung constitutes a niche not only for activated T cells but also for resting myelin-reactive memory T cells. After local stimulation in the lung, these cells strongly proliferate and, after assuming migratory properties, enter the CNS and induce paralytic disease. The lung could therefore contribute to the activation of potentially autoaggressive T cells and their transition to a migratory mode as a prerequisite to entering their target tissues and inducing autoimmune disease.
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Gene Expression Omnibus
The data discussed in this publication have been deposited in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus and are accessible through GEO Series accession number GSE38645 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc5GSE38645).
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The authors thank A. Stas, S. Hamann, N. Meyer and I. Haarmann for technical assistance. N. Plesnila supported this work with advice in surgical preparations; T. Issekutz provided anti-CXCR3 and anti-VLA4 monoclonal antibodies. We are grateful to D. Johnson and F. Lühder for critical reading of the manuscript. We thank W. Leibold for critical discussions. We thank C. Ludwig for text editing. Hartmut Wekerle is Senior Research Professor of the Hertie Foundation. This work was supported by the Deutsche Forschungsgemeinschaft (TRR-SFB43, FORR 1336), the Bundesministerium für Bildung und Forschung (‘UNDERSTAND MS’) and the Hertie Foundation (grant 1.01.1/11/004).
The authors declare no competing financial interests.
This file contains Supplementary Figures 1-10. (PDF 22336 kb)
This file contains a movie showing intravital 2-PM imaging of Tblast cells or Tmigratory cells arriving at the leptomeninges during early tEAE. In vivo recording of Tblast cells was performed 24, 48 and 72h p.t. Tmigratory cells were recorded at 5 minutes, 24 and 48h p.t. Green: TMBP-GFP cells. Red: Texas Red labeled vessels. (MOV 19769 kb)
This file contains a movie showing TMBP-GFP cell motility within the lung parenchyma. 2-PM imaging of TMBP-GFP cells in ex-vivo lung slices 5 minutes, 24, 48 and 72h p.t. 3D reconstruction and correspondent Z-projection (video to the right). Green: TMBP-GFP cells. Blue: collagen. Recording time: 1h. (MOV 30442 kb)
This file contains a movie showing TMBP-GFP cell motility within the BALT. 3D reconstruction of movement of TMBP-GFP cells recorded by 2-PM 72h p.t. in ex-vivo lung slices. The video to the right shows the motility in the Z- projection. Green: TMBP-GFP cells. Blue: second harmonic generation imaging of collagen. Recording time: 1h. (MOV 30437 kb)
This file contains a movie that shows TMBP-GFP cells migrate along the airways. It shows 3-D reconstruction of TMBP-GFP cell locomotion along and within a bronchial structure and correspondent Z-projections. Green and red: TMBP-GFP cells migrating outside and inside the airways respectively. Blue: collagen. Video was recorded by 2-PM for 1h. (MOV 30600 kb)
This file contains a movie that shows homophilic ninjurin-1 interactions contribute to intraluminal TMBP-GFP cell crawling. Intravital imaging of TMBP-GFP cell motility in the leptomenigeal vessels at 60h p.t. was performed before and 90 minutes after injection of Ninj16-45 peptide. Left video: T cell motility. Right video: time laps projections. Green: TMBP-GFP cells. Red: Texas Red labeled vessels. Note that after Ninjurin-1 blocking peptide treatment the extravascular tracks (white lines) are maintained whereas the intravascular ones (yellow lines) are shorter or dotted-like, indicating that TMBP-GFP cells crawl for less time or roll along the vessel walls. (MOV 8331 kb)
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Odoardi, F., Sie, C., Streyl, K. et al. T cells become licensed in the lung to enter the central nervous system. Nature 488, 675–679 (2012). https://doi.org/10.1038/nature11337
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