A team of researchers at the RIKEN Center for Integrative Medical Sciences (IMS) and Kyoto University in Japan has discovered several types of rare helper T cells that are associated with immune disorders such as multiple sclerosis and rheumatoid arthritis.
The research, led by Yasuhiro Murakawa, systems biologist at RIKEN-IFOM Joint Laboratory for Cancer Genomics, which was published July 4 in Science, leverage a new technology the team developed a method called ReapTEC that allowed them identify rare enhancer RNAs (eRNAs) to build a CD4+ T cell type–resolved multimodal atlas to pinpoint genetic and cellular causes of immune-mediated diseases.
The authors noted that helper T cells make up a large and important portion of the immune system helping to recognize pathogens and regulate immune response. While much is known about many common T cells, new research has pointed toward rare and specialized types of T cells that could be related to immune mediation and autoimmunity.
Enhancers are regions within DNA that do not code for proteins, instead coding for small pieces of RNA that enhance the expression of other genes. Variations in T cell enhancer DNA therefore lead to differences in gene expression, which can have a follow on effect influencing the function of T cells. Some enhancers are bidirectional—both strands of DNA are used as templates for eRNA. ReapTEC was developed by the researchers to look for connections between bidirectional T cell enhancers and immune diseases.
In their work, the investigators used the technology to analyze roughly one million human T cells and found a number of rare T cell types that accounted for less than five percent of the total. This analysis revealed nearly 63,000 active bidirectional enhancers. They then used their data to compare them to published genome-wide association studies (GWAS) that have identified single-nucleotide polymorphisms (SNPs) related to immune diseases.
After combining their ReapTEC analysis with GWAS data, they discovered that some genetic variants for immune-mediated diseases were often located in within the bidirectional enhancer DNA of the rare T cells the team had identified. Diving deeper the researchers were able to demonstrate that specific individual enhancers were related to specific immune diseases. Their comparison of the GWAS data with the 63,000 bidirectional enhancers they had identified allowed them to narrow the field down to 606 SNPs associated with 18 immune diseases.
Importantly, the team identified some of the genes that are targets of the disease-related enhancers noting, for instance that when they activated an enhancer for a variant related to inflammatory bowel disease (IDB), the eRNA produced upregulation of the IL7R gene. IBD is often treated with tumor necrosis factor (TNF) inhibitor therapies. But many patients don’t respond to these regimens as research has shown that high expression of both IL7R and IL-7R signaling signature in the colon before treatment for IBD has been strongly associated with non-responsiveness to these forms of treatment. The RIKEN team’s discovery, therefore, provides a potential new avenue for the development of IBD treatments.
“In the short-term, we have developed a new genomics method that can be used by researchers around the world,” said 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.”
