Rare types of helper T cells uncovered

Numerous rare types of helper T cells, associated with immune disorders like rheumatoid arthritis and multiple sclerosis (MS), have been discovered by scientists at the RIKEN Center for Integrative Medical Sciences (IMS), Kyoto University and IFOM ETS. The new T cell atlas, now publicly available, could aid the development of novel drug therapies for immune-mediated diseases.

Many immune mediated diseases are caused by abnormal T cell function. In autoimmune conditions such as MS, they mistakenly attack parts of the body as if they were pathogens. Like in all cells, T cells have regions of DNA termed “enhancers” which code for pieces of RNA and enhance expression of other genes. Therefore, T-cell enhancer DNA variations result in differences in gene expression, which influences T cells’ function. Some enhancers are bidirectional, meaning both DNA strands are used as templates for enhancer RNA. The researchers’ new ReapTEC technology was developed to search for associations between bidirectional T cell enhancers and specific immune disorders.

Following analysis of around a million human T cells, the researchers discovered several groups of rare T cell types, accounting for less than five percent of the total. Almost 63,000 active bidirectional enhancers were identified by applying ReapTEC to these cells. They then investigated genome-wide association studies (GWAS), which have reported many single-nucleotide polymorphisms related to immune diseases. The GWAS data was combined with the ReapTEC analysis results, which uncovered that genetic variants for immune-mediated diseases were frequently located within the bidirectional enhancer DNA of the rare T cells that they had identified. However, genetic variants for neurological diseases did not show a similar pattern, demonstrating that the bidirectional enhancers in these rare T cells are related specifically to immune-mediated diseases.

Furthermore, the team showed that individual enhancers in particular rare T cells are related to certain immune diseases. Overall, among the 63,000 bidirectional enhancers, they were able to find 606 that included single-nucleotide polymorphisms related to 18 immune-mediated diseases. Notably, genes that are the targets of these disease-related enhancers were found. For example, when the scientists activated an enhancer containing  a genetic variant related to inflammatory bowel disease, the resulting enhancer RNA initiated upregulation of the IL7R gene.

Dr Yasuhiro Murakawa, the study’s leader, concluded: “In the short-term, we have developed a new genomics method that can be used by researchers around the world…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.”

This study was published in Science.