Researchers discover rare type of helper T cell linked to immune disease

Researchers led by Yasuhiro Murakawa of the RIKEN Center for Integrative Medical Sciences (IMS) and Kyoto University, and IFOM ETS in Italy, have discovered several unusual types of helper cells. T cells It is linked to immune disorders such as multiple sclerosis, rheumatoid arthritis, and even asthma. ScienceThe discovery was made possible by a newly developed technique they call ReapTEC, which identifies genetic enhancers in rare T cell subtypes associated with specific immune diseases. The new T cell atlas is now 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 make up the majority of the immune system. They recognize pathogens and control the immune response. Many immune-mediated diseases are caused by abnormal functioning of T cells. In autoimmune diseases such as multiple sclerosis, T cells 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. Although several common T cells are known, recent studies have shown that rare and specialized types of T cells exist and may be related to immune-mediated diseases.

All cells, including T cells, have regions of DNA called “enhancers.” This DNA does not code for proteins. Instead, it codes for small pieces of RNA that enhance the expression of other genes. Therefore, mutations in T cell enhancer DNA can lead to differences in gene expression and affect T cell function. Some enhancers are bidirectional, meaning that both strands of DNA are used as templates for the enhancer RNA. Researchers from several different laboratories at RIKEN IMS, along with colleagues from other institutes, collaborated to develop the new ReapTEC technology to explore the relationship between bidirectional T cell enhancers and immune diseases.

After analyzing approximately one million human T cells, we found a small group of rare T cell types that make up less than 5% of the total. By applying ReapTEC to these cells, we identified approximately 63,000 bidirectional enhancers. To investigate whether any of these enhancers are associated with immune diseases, we turned to genome-wide association studies (GWAS), which have reported a large number of genetic variants, called single nucleotide polymorphisms, that are associated with various immune diseases.

When the researchers combined their GWAS data with the results of their ReapTEC analysis, they found that immune-mediated disease genetic variants frequently reside within the bidirectional enhancer DNA of the rare T cells they identified. In contrast, neurological disease genetic variants did not show a similar pattern, implying that these rare T cell bidirectional enhancers are specifically relevant to immune-mediated diseases.

The researchers dug deeper into the data and showed that individual enhancers in specific rare T cells were associated with specific immune diseases. Overall, they were able to identify 606 of the 63,000 bidirectional enhancers, including single nucleotide polymorphisms associated with 18 immune-mediated diseases. Finally, the researchers were able to identify some of the genes targeted by these disease-associated enhancers. For example, when activating an enhancer containing a genetic mutation associated with inflammatory bowel disease, the resulting enhancer RNA IL7R gene.

“In the short term, we have developed a new genomic analysis method that can be used by researchers around the world. Using this method, we have discovered new types of helper T cells and genes associated with immune diseases. We hope that this knowledge will lead to a better understanding of the genetic mechanisms underlying immune-mediated diseases in humans.”

Yasuhiro Murakawa, RIKEN Center for Integrative Medical Sciences

In the longer term, the researchers hope that further experiments may identify new molecules that could be used to treat immune-mediated diseases.