The scientists discovered that the aggressive T-cells overcome the barrier between blood and nerve tissue in a number of steps. Outside the nervous system, the labelled cells moved just as we would expect them to; most cells were floating along with the flow of the bloodstream. Only now and again did a cell attach itself briefly onto the vascular wall. Here they rolled in the direction of the blood stream or were being carried off again by the current. Yet, once the cells reached the blood vessels of the nervous system, they began to act in a completely different manner. The scientists observed here far more cells clinging to the vascular walls. "Things got really exciting when we observed that the cells can actually creep, a behaviour so far unheard of for T-cells", Ingo Bartholomäus relates his observations. Here, "creeping" describes an active cell movement, usually against the flow of the bloodstream. The scientists watched T-cells as they took anything between a few minutes and several hours to creep along the vessels' walls. At the end of such a search movement, the cells were either swept away again by the bloodstream or they managed to squeeze through the vascular wall.
Ominous encounters
Having successfully penetrated the blood-brain-barrier, the cells continued their search in the vicinity of the blood vessels. It was thus only a question of time before the T-cells encountered one of the phagocytic cells abundant on the outer linings of blood vessels and on the surface of the nerve tissue. When a mobile T-cell came across such a phagocyte, the two cells formed a closely connected pair. Some of these pairs remained inseparable for several minutes.
Although the scientists already knew that T-cells must make contact with phagocytes in order to become immune-activated, they were now able to observe these interactions right where they happened, i.e. at the blood-brain-barrier. And indeed, the T-cells did not launch their attack on the nervous system by releasing their inflammatory neurotransmitters until they had bonded with the phagocytes. As a result of the T-cells' activation, more and more T-cells passed through the vascular walls. "The activation of T-cells at the border to the nerve tissue appears to be a decisive signal for the invasion of the immune cells", concludes Alexander Flügel, supervisor of the study and director of the Department of Experimental and Clinical Neuroimmunology at the University Medical Center Göttingen and Head of the MS Hertie-Institute.
Light bulb moments
Thanks to their sophisticated observation methods, the scientists also established that some of the antibodies already being used in MS-therapy cause the creeping cells to disappear. As Ingo Bartholomäus explains "Up to now, it was only known that these antibodies prevented the T-cells' escaping from the blood vessels, but as our observations now show, they actually prevent them from creeping".
Thanks to the scientists' observations, we now have a much clearer picture of how the immune cells move and obtain access to the nervous system. This knowledge is likely to also increase our knowledge of the immune system's security system functions in healthy tissue. However, as is often the case, new insights and information also give rise to many new questions. How do the immune cells manage to cling to the lining of the blood vessels and how do they recognize the weak spots, where they can slip through the barrier between the bloodstream and the nervous system? What governs the cells once they have surmounted the blood-brain-barrier? These are some of the questions the scientists will be addressing next. The long-term goal will be to develop new forms of therapy and medication for multiple sclerosis and other diseases.
The film shows in real time how the green labeled T-cells creep along the inside walls of blood vessels before single cells force their way through the vessels' walls and penetrate the nerve tissue.
(Photo Credit: Max Planck Institute of Neurobiology / Bartholomäus)
The picture shows the movement of creeping T-cells (green) inside blood vessels (red) over a period of about 20 minutes. It clearly shows that some T-cells leave the blood vessels -- the long exposure lets them leave a green trail as the cells make their way through the brain tissue.
(Photo Credit: Image: Max Planck Institute of Neurobiology / Bartholomäus)
Source: Max-Planck-Gesellschaft