Understanding the Role of Tet Proteins in Autoimmune Disorders

While the genesis of autoimmune diseases remains unknown, researchers from Osaka University published an article in the journal Nature Immunology that describing how the role of specific Tet proteins in the catalyzation of reversible changes to our DNA that can cause autoimmune disorders, while the absence of the same proteins drives autoimmunity.  

The tet-eleven translocation (Tet) protein family is known to demethylate DNA, decreasing the production of specific proteins within immune cells.  While the role of Tet proteins in autoimmune illnesses had been hypothesized, the study shares important insights as to how epigenetics contributes to the development of autoimmune disorders. 

"Epigenetics deals with how reversible changes in DNA affect gene activity and protein expression," says the corresponding author of the study Tomohiro Kurosaki. "Disrupting this machinery can have dramatic effects on cellular function. The goal of our study was to understand how epigenetic control in a specific type of immune cells, called B cells, affects the development of autoimmune diseases."

"We wanted to gain a deeper molecular understanding of the mechanism behind the effects of Tet2 and Tet3 on the immune system,” says Shinya Tanaka, lead author. In order to do so, the team developed a novel mouse line in which B cells were mutated to inhibit the production of epigenetic regulator proteins Tet2 and Tet3. The results showed that these mice developed systemic lupus erythematosus, negatively impacting the skin, kidneys, organs, and joints. 

The next step involved looking at T cells because of their common interaction with B cells. Their findings showed that T cell activity was exacerbated by the Tet2/Tet3 inhibited mice. The team was able to further identify that the protein CD86 was produced at worrying levels within the mice, which led to failed T-cell activation. 

"These are striking results that show how Tet proteins suppress autoimmune diseases by inactivating B cells and thus ultimately preventing them from attacking our bodies," says Kurosaki. "Our findings provide new insights into the contribution of epigenetics to the development of autoimmune disease. Regulating Tet proteins and their downstream effectors could be a novel treatment for autoimmune diseases."