T cells become licensed in the lung to enter the central nervous system.
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 BBB 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 parenchyma. 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.
Institute for Multiple Sclerosis Research, Department of Neuroimmunology, Gemeinnützige Hertie-Stiftung and University Medical Centre Göttingen, 37073 Göttingen, Germany.
Francesca
F
Odoardi
Christopher
C
Sie
Kristina
K
Streyl
Vijay K
VK
Ulaganathan
Christian
C
Schläger
Dmitri
D
Lodygin
Klaus
K
Heckelsmiller
Wilfried
W
Nietfeld
Joachim
J
Ellwart
Wolfgang E F
WE
Klinkert
Claudio
C
Lottaz
Mikhail
M
Nosov
Volker
V
Brinkmann
Rainer
R
Spang
Hans
H
Lehrach
Martin
M
Vingron
Hartmut
H
Wekerle
Cassandra
C
Flügel-Koch
Alexander
A
Flügel
D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D001812:Blood-Brain Barrier / Q000276:immunology; D001921:Brain / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002465:Cell Movement; D002560:Cerebrovascular Circulation; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology*; D020869:Gene Expression Profiling; D007156:Immunologic Memory; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D008213:Lymphocyte Activation; D009186:Myelin Sheath / Q000276:immunology; D009414:Nerve Growth Factors / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
D015816:Cell Adhesion Molecules, Neuronal; D009414:Nerve Growth Factors; C101196:Ninj1 protein, rat