Researchers led by Yasuhiro Murakawa at the RIKEN Center for Integrative Medical Sciences (IMS) and Kyoto University in Japan and IFOM ETS in Italy have discovered several rare types of helper T cells that are associated with immune disorders such as multiple sclerosis, rheumatoid arthritis, and even asthma. Published July 4 in ScienceThe discoveries were made possible by a newly developed technology called ReapTEC, which identified genetic enhancers in rare T cell subtypes that are linked to specific immune disorders. The new T cell atlas is publicly available and should aid in the development of new drug therapies for immune-mediated diseases.
Helper T cells are a type of white blood cell that is an important part of the immune system. They recognize pathogens and regulate the immune response. Many immune-mediated diseases are caused by abnormal T cell function. In autoimmune diseases, such as multiple sclerosis, they mistakenly attack parts of the body as if they were pathogens. In allergies, T cells overreact to harmless substances in the environment, such as pollen. We know of several common T cells, but recent studies have shown that there are rare, specialized types of T cells that may be involved in immune-mediated diseases.
In all cells, including T cells, there are regions of DNA called “enhancers.” This DNA does not code for proteins, but rather for small RNA fragments that boost the expression of other genes. Variations in T cell enhancer DNA therefore lead to differences in gene expression, which can affect how T cells function. Some enhancers are bidirectional, meaning that both strands of DNA are used as templates for the enhancer RNA. Researchers from several different RIKEN IMS labs, as well as colleagues from other institutes, teamed up to develop the new ReapTEC technology and search for connections between bidirectional T cell enhancers and immune diseases.
After analyzing nearly a million human T cells, they found several clusters of rare T cell types, which account for less than 5% of the total. By applying ReapTEC to these cells, they identified nearly 63,000 active bidirectional enhancers. To find out if any of these enhancers are linked to immune diseases, they turned to genome-wide association studies (GWAS), which have reported numerous genetic variants, called single nucleotide polymorphisms, that are linked to a variety of immune diseases.
When the researchers combined the GWAS data with the results of their ReapTEC analysis, they found that genetic variants for immune-mediated diseases were often located within the bidirectional enhancer DNA of the rare T cells they had identified. In contrast, genetic variants for neurological diseases did not show a similar pattern, meaning that the bidirectional enhancers in these rare T cells are specifically linked to immune-mediated diseases.
Digging even deeper into the data, the researchers were able to show that individual enhancers in certain rare T cells are linked to specific immune diseases. Overall, among the 63,000 bidirectional enhancers, they were able to identify 606 that included single nucleotide polymorphisms linked to 18 immune-mediated diseases. Finally, the researchers were able to identify some of the genes that are targeted by these disease-related enhancers. For example, when they activated an enhancer that contained a genetic variant linked to inflammatory bowel disease, the resulting enhancer RNA triggered upregulation of the IL7R gene.
“In the short term, we have developed a new genomic method that can be used by researchers around the world,” says Murakawa. “Using this method, we discovered new types of helper T cells as well as genes related to immune disorders. We hope that this knowledge will lead to a better understanding of the genetic mechanisms underlying human immune-mediated diseases.”
In the long term, researchers believe that follow-up experiments may identify new molecules that can be used to treat immune-mediated diseases.