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

Abstract

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.

Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy

“…1D). Both T MBP-Twitch1 and T OVA-Twitch1 cells were also imaged in the lung, where encephalitogenic T cells first accumulate and initiate their licensing process (6). Calcium signaling in both types of lung resident T cells was extremely low, even lower than seen in the spleen (Fig.…”

“…The T cells settle in the splenic paracortical milieu, where they perambulate apparently at random, making brief contacts with local stroma cells (5,16). During their sojourn, in the absence of specific autoantigens, the T cells radically rearrange their gene expression profile, acquiring a specialized phenotype that facilitates their passage through the BBB (5,6). The nature of the signals that initiate and drive this differentiation has remained open so far.…”

“…Fully activated myelin-specific T cells do not directly enter the CNS parenchyma; they first have to spend time in the periphery (22), where they become licensed for CNS invasion (5,6). The first milieus visited by T-cell blasts after i.v.…”

“…After activation in a remote peripheral site, such as in the intestine (4), they first spend a brief time in secondary (2°) lymphatic organs and then cross the endothelial BBB and finally reach their ultimate destination, the CNS white matter. In the lymph nodes, lung, and spleen, freshly activated T cells acquire a functional phenotype that enables them to successfully overcome the cerebrovascular BBB (5,6). Beyond the vascular barrier, the T cells are confronted with phagocytes that, by presenting myelin autoantigen, usher them into the compact CNS white matter (7)(8)(9).…”

Urban air quality and associations with pediatric multiple sclerosis

“…This could also lead to oxidative stress and permeability in the epithelial walls allowing access of foreign particles into the blood stream 2. Furthermore, pollutants might stimulate immune response with activating potentially auto‐aggressive T‐cells to enter the central nervous system 25. Second, the inhaled particles could be translocated through the olfactory system and cross the blood–brain barrier.…”