Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery.
Ito M, Komai K, Mise-Omata S, Iizuka-Koga M, Noguchi Y, Kondo T, Sakai R, Matsuo K, Nakayama T, Yoshie O, Nakatsukasa H, Chikuma S, Shichita T, Yoshimura A
Nature. 2019 Jan;565(7738):246-250
Key Points:
a) Inflammation can occur with any brain injury. This includes stroke as well as MS.
b) Inflammation in the brain can be both good and bad. In MS, inflammation results in tissue destruction. However, inflammatory cells also are needed to remove damaged tissue and allow better healing.
c) Though this paper deals with an animal model of stroke, the findings have relevance to MS.
d) After stroke in mice many immune cells, called T cells, enter the brain at the site of tissue injury.
e) There are many types of T cells, each with different functions. One population of T cells is called “regulatory T cells” or Treg. Such cells control the function of other T cells. They are decreased in persons with MS, allowing tissue-damaging T cells to function more freely.
f) Right after a stroke, numbers of Treg in mouse brains were very low. However, two weeks later numbers of Treg cells at the site of injury greatly increased, and continued to increase thereafter.
g) When production of Treg cells was prevented, or when Treg cells were kept from entering the brain with the drug FTY720 (also known as the MS drug fingolimod), brain scarring (astrogliosis) and loss of nerve cells was greatly increased.
h) Thus, the appearance of Treg cells weeks after tissue injury resulted in reduced brain injury and less tissue destruction.
i) Preliminary studies in mice affected with an animal model of MS, experimental autoimmune encephalomyelitis, showed similar changes, that is by raising numbers of Treg cells brain scarring was reduced.
j) Since Tregcells may be important in decreasing tissue damage and promoting recovery in MS, how do we “fine tune” MS treatments so that they don’t suppress the entire immune system, as now happens, but instead selectively kills damaging immune cells while sparing immune cells that increase brain healing? Much work needs to be done.
The immune system is a double-edged sword. It protects us from invading organisms, but when turned against its host it can wreck havoc. The immune system changes during an immune response, regulating itself so that the response does not go on forever. Much of the regulation of immune responses comes from cells of the immune system and their products. One important group of regulating cells is Treg cells. The above paper shows in excellent detail that the initial inflammation in stroke-injured brain tissue causes nerve cells (neurons) to be lost and brain cells called astrocytes to be activated or “turned on”, and to multiply. This reaction, called “astrogliosis,” results in the formation of dense, permanent scars. Such scarring also occurs in MS, resulting in the formation of brain plaques that are characteristic of the disease.
Over several weeks the immune cells entering the brains of these mice changed, with gradually increasing numbers of regulatory T cells, or Treg, appearing in areas of tissue injury. Their appearance was associated with less brain injury and less activation of astrocytes, with less scarring. The authors of the paper were able to show how Treg cells reduced astrocyte activation and also showed that Treg cells in the brain were different than Treg cells elsewhere in the body. They appeared to be drawn to the brain in response to an unknown brain substance. Identifying this substance could result in a potential treatment for MS, since giving this substance to persons with MS could result in attracting beneficial immune cells to sites of tissue damage.
There is, however, a greater challenge. All currently approved disease-modifying therapies for MS involve a modulation or suppression of the immune system that is not specific. In other words, all cells, both tissue-damaging cells and beneficial immune cells are affected. In rare cases this has resulted in worsening of disease. While reasons for worsening of disease with immune modulating therapies are not known, based on the results of the above paper, one possibility is that these drugs affected not only harmful immune cells, but also beneficial immune cells that protected tissues and allowed tissue repair. There is no doubt that major advances in the treatment of relapsing forms of multiple sclerosis have occurred in the past several decades, but much work still needs to be done.
Paper's Abstract is available.