Researchers led by Yasuhiro Murakawa of 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 associated with immune disorders such as multiple sclerosis, rheumatoid arthritis, and even asthma. Published July 4 in the journal Science, the findings were made possible by a new technology called ReapTEC, which identified genetic enhancers in rare T cell subtypes linked to specific immune disorders. The new T cell atlas is publicly available and is expected to aid in the development of new drug therapies for immune-mediated diseases.
Helper T cells are white blood cells that make up a large part of the immune system. They recognize pathogens and regulate the immune response. Many immune-mediated diseases are caused by abnormal functioning of T cells. 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 and specialized types of T cells that may be linked to immune-mediated diseases.
In all cells, including T cells, there are regions of DNA called “enhancers.” This DNA does not code for proteins, but for small pieces of RNA, and enhances the expression of other genes. Variations in T cell enhancer DNA therefore lead to differences in gene expression, which can affect how the 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 labs at RIKEN IMS, along with colleagues from other institutes, have teamed up to develop the new ReapTEC technology and look for links between bidirectional T cell enhancers and immune diseases.
After analyzing about a million human T cells, they identified several groups of rare T cell types, representing less than 5% of the total. Applying ReapTEC to these cells identified nearly 63,000 active bidirectional enhancers. To determine whether 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 various immune diseases.
By combining the GWAS data with the results of their ReapTEC analysis, the researchers found that the genetic variants for immune-mediated diseases were often located in the bidirectional enhancer DNA of the rare T cells they identified. In contrast, the 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 deeper into the data, the researchers were able to show that individual enhancers in some rare T cells are linked to specific immune diseases. In total, of 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 the targets of these disease-related enhancers. For example, when they activated an enhancer containing 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 genomics method that can be used by researchers around the world,” Murakawa says. “Using this method, we have 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 diseases.”
In the long term, the researchers believe that follow-up experiments will identify new molecules that can be used to treat immune-mediated diseases.
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