The immune system plays an essential role in protecting the human body from infection/disease. It attacks germs that have entered our bodies and remembers previously encountered pathogens so it can better fight off those pathogens if they are encountered again. Two kinds of immune cells are important for this process: B and T lymphocytes. B lymphocytes are like the body's military intelligence system — they find their targets and send defenses to lock onto them. T lymphocytes, on the other hand, are like the soldiers, in that they destroy the invaders that the intelligence system finds.

Many proteins work together to ensure that the immune system works properly; however, when one of these proteins is lost or becomes non-functional, problems within our immune system arise. One of these problems is autoimmunity, where our immune system essentially becomes our own worst enemy, as it mistakes healthy cells as foreign pathogens and attacks them. Both T and B cells often become overactive in autoimmunity, failing to tell the difference between healthy and infected cells and indiscriminately killing all cells within the body. The increasing prevalence of autoimmunity has caused many to focus on how these conditions arise.

The authors had previously reported that high levels of a protein, called capicua (CIC), was found within multiple types of immune cells.Thus, they hypothesized that CIC could be one of the factors involved in regulating the processes of the immune system. To investigate this, they removed CIC from all “precursor” cells that eventually mature into immune cells in mice. As a result, they observed many characteristics that were indicative of autoimmunity, including enlarged/inflamed immune organs such as the spleen and infiltration of immune cells into non-immune related body tissue.

Every B cell has unique receptors on the cell surface that respond to specific foreign pathogens that the body has previously encountered. Germinal Centers (GCs) are sites where the body chooses specific B cells depending on what pathogen enters the body. Selected B cells will then mature in these GCs with the help of specialized cells called follicular helper T (T_FH) cells. High amounts of these T_FH cells and B cells within GCs are a common indicator of autoimmunity. By measuring levels of certain cell surface markers unique to T_FH cells, the authors were able to estimate how many T_FH cells were present at these GCs. They found that in the absence of CIC, the mice had higher levels of T_FH cells compared to their normal counterparts.

These results were further reinforced by measuring surface markers unique to B cells at GCs. They showed that CIC deficient mice had a higher number of B cells at these GCs compared to healthy mice. Essentially, both results show that there are more B cells within GCs, and they are being selected more frequently and less discriminately, thus misdirecting the immune system to attack our healthy cells.

Furthermore, the authors explored the effects caused by removing CIC exclusively within T cells. They observed the same results as when they removed CIC from all immune cells. From these experiments,the authors concluded that these autoimmune characteristics and the overactive GCs were directly caused by CIC deficiency in T cells.

Next, instead of focussing on GCs and B cells, the authors turned their attention towards another crucial aspect of the immune system, the T cells. More specifically, they focussed on regulatory T (T_reg) cells (a special kind of T cells) that are crucial mediators of autoimmunity, as they suppress the immune system in critical times to ensure that it does not attack healthy cells. Abnormal number of these T_reg cells implies a dysfunctional immune system and autoimmunity. Similar to the experiments with the T_FH cells, the authors measured the frequency of these T_reg cells in normal mice and mice lacking CIC in T cells. They observed that a CIC deficiency causes an activation of certain genes that helps increase the maturation and propagation of T_reg cells, causing an abnormal frequency of T_reg cells to develop. Once again, they demonstrated that an absence of CIC causes these phenotypes characteristic of autoimmunity.

In conclusion, the authors demonstrated that a loss of CIC induces systemic autoimmunity by creating overactive GCs, and increased frequency of T_FH and T_reg cells, common indicators of autoimmunity. CIC, and the downstream proteins the authors also identified that are important to triggering this autoimmune response, can be studied in the future as possible avenues for treating systemic autoimmunity and the complications it can cause.

Reference:

Park, S. et al. Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5. Nat Commun 8, 16037 (2017). Link to the full text article.