Unlocking the Secrets of Rare Helper T Cells: A New Frontier in Immune Disorder Research
Researchers led by Yasuhiro Murakawa at the RIKEN Center for Integrative Medical Sciences (IMS) and Kyoto University in Japan, along with IFOM ETS in Italy, have made groundbreaking discoveries in the realm of immune disorders. Their findings, published on July 4 in Science, shed light on several rare types of helper T cells that are closely linked to conditions such as multiple sclerosis, rheumatoid arthritis, and asthma. This pivotal research was made possible by the innovative technology known as ReapTEC, which identified genetic enhancers in these rare T cell subtypes associated with specific immune disorders. The newly unveiled T cell atlas, now publicly available, holds the promise of revolutionizing the development of novel drug therapies for immune-mediated diseases.
Helper T cells, a type of white blood cell integral to the immune system, play a crucial role in recognizing pathogens and regulating immune responses. Dysfunction in T cells is often the root cause of many immune-mediated diseases. In the case of autoimmune conditions like multiple sclerosis, these cells mistakenly attack the body’s own tissues as if they were foreign invaders. Similarly, in allergies, T cells exhibit an exaggerated response to harmless substances in the environment, such as pollen. While common types of T cells are well-known, recent studies have unveiled the existence of rare and specialized T cell subsets that may be closely tied to immune disorders.
At the core of all cells, including T cells, lie regions of DNA called enhancers. Unlike coding DNA that produces proteins, enhancer DNA generates small RNA molecules that enhance the expression of other genes. Variability in T cell enhancer DNA can lead to variations in gene expression, thereby influencing T cell functionality. Some enhancers are bidirectional, meaning both strands of DNA serve as templates for enhancer RNA. Collaborating across different laboratories at RIKEN IMS and beyond, researchers developed ReapTEC to unearth connections between bidirectional T cell enhancers and immune diseases.
Through the analysis of approximately one million human T cells, researchers identified several rare T cell subgroups, constituting less than 5% of the total T cell population. Leveraging ReapTEC on these cells revealed nearly 63,000 active bidirectional enhancers. To ascertain the association between these enhancers and immune diseases, researchers integrated genome-wide association studies (GWAS) data, which pinpoint genetic variants (single-nucleotide polymorphisms) linked to various immune disorders.
Upon juxtaposing the GWAS data with the outcomes of the ReapTEC analysis, researchers found that genetic variants associated with immune-mediated diseases were frequently located within the enhancer DNA of the rare T cell subsets identified. Conversely, genetic variants for neurological conditions did not exhibit a similar pattern, indicating a specific correlation between bidirectional enhancers in rare T cells and immune disorders.
Delving deeper into the data, researchers uncovered that individual enhancers within specific rare T cells were linked to distinct immune diseases. Out of the 63,000 bidirectional enhancers, 606 encompassed single-nucleotide polymorphisms related to 18 immune-mediated diseases. Furthermore, researchers pinpointed some of the genes targeted by these disease-related enhancers. For instance, activation of an enhancer containing a genetic variant associated with inflammatory bowel disease led to the upregulation of the IL7R gene.
Yasuhiro Murakawa emphasized the significance of their findings, stating, “In the short-term, we have developed a new genomics method that can be utilized by researchers globally. Through this approach, we have discovered novel types of helper T cells and genes implicated in immune disorders. We anticipate that this knowledge will enhance our understanding of the genetic mechanisms underpinning human immune-mediated diseases.”
Looking ahead, researchers believe that follow-up experiments will unearth new molecules with the potential to transform the treatment of immune-mediated diseases.
