A team of researchers have found several unique types of helper T cells linked to immune disorders like multiple sclerosis, rheumatoid arthritis, and asthma. This breakthrough was made possible through a novel technology called ReapTEC. The findings, detailed in a recent publication in Science, have unveiled a new T cell atlas that is now publicly accessible and is expected to aid in the development of innovative drug treatments for immune-related conditions.
Helper T cells, a crucial component of the immune system, play a pivotal role in recognizing and regulating the immune response to pathogens. Abnormalities in T cell function are often at the root of immune-mediated diseases. For instance, in autoimmune conditions such as multiple sclerosis, T cells erroneously attack the body’s own tissues as if they were foreign invaders. On the other hand, in allergies, T cells can overreact to harmless substances like pollen. While we are familiar with common types of T cells, recent research has shed light on the existence of rare and specialized T cell subtypes that might be connected to immune disorders.
In every cell, including T cells, there are specific DNA regions known as “enhancers.” Unlike protein-coding DNA, enhancers produce small RNA molecules that regulate gene expression. Variations in enhancer DNA within T cells can impact their functionality. Some enhancers are bidirectional, meaning they use both DNA strands to produce RNA. Collaborating across different research labs at RIKEN IMS and other institutions, scientists developed the innovative ReapTEC technology to explore the relationship between bidirectional T cell enhancers and immune diseases.
By studying approximately a million human T cells, the researchers identified several rare T cell groups, constituting less than 5% of the total population. The application of ReapTEC revealed nearly 63,000 active bidirectional enhancers in these cells. To investigate the association between these enhancers and immune diseases, the researchers integrated genome-wide association studies (GWAS) data, which identify genetic variants associated with various immune conditions.
Upon juxtaposing the GWAS findings with the ReapTEC analysis outcomes, the researchers discovered that genetic variants linked to immune-mediated diseases were frequently situated within the bidirectional enhancer DNA of the rare T cell subsets they identified. In contrast, neurological disease-related genetic variants did not exhibit a similar pattern, showing that bidirectional enhancers in these rare T cells are particularly tied to immune-related disorders.
Further examination revealed that specific enhancers within certain rare T cells are connected to distinct immune disorders. Of the 63,000 bidirectional enhancers analyzed, 606 contained single-nucleotide polymorphisms associated with 18 immune-related diseases. Moreover, the researchers pinpointed some of the genes targeted by these disease-related enhancers. For instance, activating an enhancer containing a genetic variant linked to inflammatory bowel disease led to upregulation of the IL7R gene.
Lead researcher Murakawa highlights, “In the short term, we have developed a new genomics technique that can benefit researchers globally. Through this approach, we unearthed novel helper T cell types and genes associated with immune disorders. We anticipate that this knowledge will enhance our understanding of the genetic mechanisms underlying human immune-mediated diseases.”
In the long term, the researchers anticipate that subsequent experiments will enable the identification of new molecules for treating immune-related conditions.
