Yasuhiro Murakawa’s team of researchers at the RIKEN Centre for Integrative Medical Sciences (IMS), Kyoto University in Japan, and IFOM ETS in Italy have identified several uncommon helper T cell subtypes that are linked to immune conditions like asthma, rheumatoid arthritis, and multiple sclerosis.
Their findings were published in the journal Science.
The findings were made feasible by a recently created technique known as ReapTEC, which found genetic enhancers in uncommon T cell subtypes associated with particular immunological diseases. Publicly accessible, the updated T cell atlas should aid in the creation of novel pharmacological treatments for immune-mediated illnesses.
Assistant an important component of the immune system are T cells, which are a kind of white blood cell. They control the immune response and identify infections. Atypical T cell function is the root cause of many immune-mediated diseases. Autoimmune illnesses such as multiple sclerosis cause the body to wrongly target healthy body components as infections. When it comes to environmental allergens such as pollen, T cells tend to overreact. While there are a number of common T cell kinds that are known to exist, new research has shown the existence of unusual and specialised T cell types that may be linked to immune-mediated illnesses.
All cells, including T lymphocytes, have sections of DNA known as “enhancers.” Proteins are not encoded by this DNA. Rather, it amplifies the expression of other genes and codes for short RNA segments. Thus, variations in T cell enhancer DNA result in variations in gene expression, which may have an impact on T cell function. Certain enhancers are bidirectional, meaning that enhancer RNA is transcribed from both strands of the DNA. Together with colleagues from other institutions, researchers from many laboratories at RIKEN IMS developed the novel ReapTEC technology and searched for links between immunological disorders and bidirectional T-cell enhancers.
They discovered many subsets of uncommon T cell types, making up less than 5% of the total, after examining almost a million human T cells. Using ReapTEC on these cells revealed almost 63,000 bidirectional enhancers that are activated. They looked to genome-wide association studies (GWAS) to see if any of these enhancers were linked to immunological disorders. GWAS has identified a number of genetic variations, known as single-nucleotide polymorphisms, that are linked to a variety of immune diseases.
The bidirectional enhancer DNA of the uncommon T cells that the researchers had identified frequently contained genetic variations for immune-mediated illnesses, as the researchers discovered when they integrated the GWAS data with the outcomes of their ReapTEC analysis. The bidirectional enhancers in these uncommon T cells are uniquely linked to immune-mediated illnesses, as evidenced by the lack of a comparable pattern in genetic variations for neurological disorders.
By delving even further into the data, the researchers were able to demonstrate a relationship between distinct immunological disorders and unique enhancers in certain uncommon T cells. In all, scientists were able to find 606 bidirectional enhancers out of 63,000, and those 606 comprised single-nucleotide polymorphisms linked to 18 immune-mediated illnesses. Finally, a few of the genes that these disease-related enhancers target were discovered by the researchers. For instance, the resultant enhancer RNA caused the IL7R gene to be upregulated when they activated an enhancer containing a genetic variation linked to inflammatory bowel illness.
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In the short-term, we have developed a new genomics method that can be used by researchers around the world,
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.
Yasuhiro Murakawa, Team Leader
Long-term follow-up studies, according to the researchers, should reveal novel compounds that can be used to the treatment of immune-mediated illnesses.
Source: RIKEN News
Journal Reference: Oguchi, Akiko, et al. “An Atlas of Transcribed Enhancers across Helper T Cell Diversity for Decoding Human Diseases.” Science, 2024, https://doi.org/add8394.
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