Imagine a city surrounded by impenetrable barriers. Essential supplies are transported into the city through protected gates. Small channels transport water into the city, guards specifically patrol the surrounding region while an elite group of specialized guards defend both inside and outside the city. The brain is much like this city and the immune system acts as the guards.

Cocooned in layers called the meninges, and swimming in fluid called CSF (cerebrospinal fluid), the brain receives immune cells from the bloodstream. Moving cells from the periphery into the brain is extremely regulated, barring some cells from entering while selectively permitting others through. We are beginning to understand how specific immune cells, called T cells, enter the brain through this heavily-controlled entry process. By collecting thousands of T cells from the CSF, Pappalardo et al. (2020) profiled the markers found in T cells from healthy individuals and markers found in T cells from the autoimmune disorder, Multiple Sclerosis (MS).

Profile of T cells in the brain

T cells come in many forms. Evidence is building that shows some types of T cells can enter and reside in the brain. In general, as T cells enter different tissues, they create, or express, certain structures that enable them to reside in that tissue. Recent research identified different types of T cells that potentially display markers showing this movement from circulation to the tissue by profiling T cells found in the blood and CSF. T cells in the blood were not entirely structurally unique from the brain T cells; only gradual differences were observed (Pappalardo et al., 2020). Brain-resident T cells appear to change structure over time.  The authors suggest that  T cells residing in the brain longest are most different from the blood-resident T cells.

Why does entering the brain matter?

T cells are both present and active in the brain. Identifying the proteins found on the surface of T cells enables us to uncover how T cells bind other cells in the brain, including neurons. By studying the interaction between T cells and brain-resident cells, we can discover how the immune system influences the brain.

In MS, the immune system targets and damages myelin in the brain. Like insulation encasing a pipe, neurons are ensheathed with myelin. When myelin is damaged, the brain can’t properly communicate (which ultimately is how MS patients lose muscle control as the brain can no longer communicate with muscles). In MS brains, regions that have damaged myelin have a large presence of T cells with cytotoxic (cell-killing) function called CD8 (van Nierop, et al. 2017; Salou et al, 2015) suggesting their role for damaging these myelin sheaths. Likewise, the T cells profiled in MS patients had more cytotoxic markers in the CSF compared to healthy patients (Pappalardo et al., 2020). 

Figure 1. T cells from healthy (top panel) and Multiple Sclerosis (MS; bottom panel showing damaged tissue) were profiled. As T cells (light green) move from blood vessels (top right) to the CSF (top left panel) in a healthy brain, the structures found on T cells exhibit gradual changes. Comparing the T cells found in healthy CSF (top blue portion) to MS CSF (bottom, blue portion), more markers were present for cytotoxic (cell-toxic) T cells (dark green cells).

Finding cytotoxic T cells in the CSF (Pappalardo et al. 2020) and complementary evidence that cytotoxic T cells are found in damaged regions of MS brains (van Nierop, et al. 2017; Salou et al, 2015) highlights the involvement of T cells in this autoimmune condition. Many researchers continue to identify immune cells in the brain and additionally evaluate how exactly these cells enter the brain. With this knowledge, we can continue to identify mechanisms to mitigate the damage in the brain in Multiple Sclerosis. 

Citations:

J. L. Pappalardo, L. Zhang, M. K. Pecsok, K. Perlman, C. Zografou, K. Raddassi, A. Abulaban, S. Krishnaswamy, J. Antel, D. van Dijk, D. A. Hafler, Transcriptomic and clonal characterization of T cells in the human central nervous system. Sci. Immunol. 5, eabb8786 (2020).

M. Salou, B. Nicol, A. Garcia, D.-A. Laplaud, Involvement of CD8+ T cells in multiple sclerosis. Front. Immunol. 6, 604 (2015).

G. P. van Nierop, M. M. van Luijn, S. S. Michels, M.-J. Melief, M. Janssen, A. W. Langerak,W. J. D. Ouwendijk, R. Q. Hintzen, G. Verjans, Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients. Acta Neuropathol. 134, 383–401 (2017).

The cover image for this article is courtesy of Wikimedia.