Scientists discover new T cells and genes linked to immune disorders

Researchers led by Yasuhiro Murakawa from 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 linked to immune diseases such as multiple sclerosis, rheumatoid arthritis and even asthma.

Published in ScienceThe discoveries were made possible by a newly developed technology they call 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 help in the development of new drug therapies for immune-mediated diseases.

Helper T cells are a type of white blood cell 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 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. Several common T cells are known, but recent studies have shown that rare and specialized types of T cells exist, and that these 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. Instead, it codes 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 and this can affect how T cells function. Some enhancers are bidirectional, meaning that both strands of the DNA are used as templates for enhancer RNA.

Researchers from several laboratories at RIKEN IMS and colleagues from other institutes collaborated to develop the novel ReapTEC technology and look for links between bidirectional T cell enhancers and immune diseases.

After analyzing about a million human T cells, they found several groups of rare T cell types, accounting for less than 5% of the total. By applying ReapTEC to these cells, they identified nearly 63,000 active bidirectional enhancers. To determine whether any of these enhancers were related 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.

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 in 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 related 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 related to specific immune diseases. In total, out of 63,000 bidirectional enhancers, they were able to identify 606 that contained single nucleotide polymorphisms that were related to 18 immune-mediated diseases.

Finally, the researchers were able to identify several genes that are targets of 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 the upregulation of the IL7R gene.

“In the short term, we have developed a new genomics method that can be used by researchers worldwide,” says Murakawa. “With this method, we discovered new types of helper T cells and genes related to immune disorders. We hope that this knowledge will lead to a better understanding of the genetic mechanisms underlying immune-mediated diseases in humans.”

The researchers expect that long-term follow-up experiments could identify new molecules that could be used to treat immune-mediated diseases.