Tokyo [Japan], a team of researchers has identified a number of rare T helper cell subtypes that are linked to immune conditions such as asthma, rheumatoid arthritis and multiple sclerosis.
The research carried out by Yasuhiro Murakawa's team of researchers at the RIKEN Center for Integrative Medical Sciences (IMS), Kyoto University in Japan and IFOM ETS in Italy. The findings, which were published in Science, were made possible by a newly created technique known as ReapTEC, which found genetic enhancers in rare T cell subtypes linked to particular immune diseases. The updated, publicly accessible T-cell atlas should help in the creation of new drug treatments 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 the case of 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, and they could be linked to immune-mediated diseases.
Within all cells, including T cells, there are regions of DNA called "enhancers." This DNA does not code for proteins. Instead, it encodes small fragments of RNA and enhances the expression of other genes. Therefore, variations in T cell enhancer DNA lead to differences in gene expression, and this can affect T cell function. Some enhancers are bidirectional, meaning that both strands of the DNA are used as templates. for enhancer RNA. Researchers from several different laboratories at RIKEN IMS, as well as colleagues from other institutes, came together to develop the new ReapTEC technology and look for connections between bidirectional T cell enhancers and immune diseases.
After analyzing around a million human T cells, they found several groups of rare T cell types, representing less than 5% of the total. Application of ReapTEC to these cells identified almost 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.
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 within the bidirectional enhancer DNA of the rare T cells they had identified. In contrast, genetic variants in neurological diseases did not show a similar pattern, meaning that 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 certain rare T cells are linked to specific immune diseases. Overall, among 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 target 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 genomic method that can be used by researchers around the world," says 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 immune-mediated human diseases."
The research carried out by Yasuhiro Murakawa's team of researchers at the RIKEN Center for Integrative Medical Sciences (IMS), Kyoto University in Japan and IFOM ETS in Italy. The findings, which were published in Science, were made possible by a newly created technique known as ReapTEC, which found genetic enhancers in rare T cell subtypes linked to particular immune diseases. The updated, publicly accessible T-cell atlas should help in the creation of new drug treatments 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 the case of 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, and they could be linked to immune-mediated diseases.
Within all cells, including T cells, there are regions of DNA called "enhancers." This DNA does not code for proteins. Instead, it encodes small fragments of RNA and enhances the expression of other genes. Therefore, variations in T cell enhancer DNA lead to differences in gene expression, and this can affect T cell function. Some enhancers are bidirectional, meaning that both strands of the DNA are used as templates. for enhancer RNA. Researchers from several different laboratories at RIKEN IMS, as well as colleagues from other institutes, came together to develop the new ReapTEC technology and look for connections between bidirectional T cell enhancers and immune diseases.
After analyzing around a million human T cells, they found several groups of rare T cell types, representing less than 5% of the total. Application of ReapTEC to these cells identified almost 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.
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 within the bidirectional enhancer DNA of the rare T cells they had identified. In contrast, genetic variants in neurological diseases did not show a similar pattern, meaning that 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 certain rare T cells are linked to specific immune diseases. Overall, among 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 target 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 genomic method that can be used by researchers around the world," says 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 immune-mediated human diseases."
