T cells become licensed in the lung to enter the central nervous system

A Lewis rat model of experimental autoimmune encephalomyelitis is used to show that on their way to the CNS, encephalitogenic T-cell blasts are temporarily resident in the lung, where they reprogram their gene-expression profile and functional properties to enable them to transgress the blood–brain barrier into the CNS. T-cell access to the brain via the lungs The question of how immune cells enter the brain is of central importance to understanding the physiological and pathological processes of the central nervous system (CNS). This paper describes a mechanism that allows disease-inducing effector T cells to enter the brain. In a rat adoptive-transfer model of experimental autoimmune encephalomyelitis (EAE), encephalitogenic T cells accumulate in the CNS after transient residence in the lung. On their way to the CNS, they reprogram their gene-expression profile and functional properties, ultimately enabling them to cross the blood–brain barrier. The lungs are in direct contact with the outer environment, so are a logical homing place for immune cells relevant to host defence — perhaps also providing a niche for the development of autoimmune cells. 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 1 , 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 parenchyma 3 , 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 progra