A New T Cell Atlas: Paving the Way for Advanced Therapies in Immune-Mediated Diseases

 

Immune-mediated disorders, such as multiple sclerosis, rheumatoid arthritis, and asthma, provide considerable hurdles for both individuals and healthcare systems. These disorders occur when the immune system, which is supposed to protect the body from invaders, fails and begins attacking the body's own tissues. This misguided immune response can cause persistent inflammation, tissue damage, and a variety of debilitating symptoms. For example, in autoimmune disorders such as multiple sclerosis, T cells, a kind of white blood cell, assault the body as if it were a foreign invader. Similarly, in asthma and allergies, T cells overreact to environmental stimuli such as pollen. Helper T cells are essential components of the immune system, detecting infections and regulating immune response. However, abnormal T cell function is a crucial role in many autoimmune disorders, allergies. Traditional understanding has mostly centered on common T cells, but recent research indicates that uncommon and specialized T cell types may play an important role in immune-mediated disorders.

ReapTEC, the innovative technology enables precise detection of genomic enhancers in T cells. Enhancers are DNA sequences that do not code for proteins but instead regulate the expression of other genes by producing tiny RNA molecules. Variations in enhancer DNA can cause changes in gene expression, which affects T cell activity. After studying about one million human T cells, the research discovered three groupings of uncommon T cells, which account for less than 5% of the total T cell population. Using ReapTEC, they identified approximately 63,000 active bidirectional enhancers in these cells. Additional study indicated that several of these enhancers had single-nucleotide polymorphisms (SNPs) linked to immune-mediated illnesses.

The capacity to link specific genetic variants to specific immunological disorders is what makes this strategy so powerful. The researchers identified enhancers associated with 18 distinct immune-mediated disorders by combining genome-wide association study (GWAS) data with their ReapTEC results. Using ReapTEC analysis and GWAS data, the researchers discovered that genetic variations associated with immune-mediated illnesses were frequently detected within the bidirectional enhancer DNA of these uncommon T cells. This conclusion was limited to immunological disorders, since genetic variations for neurological diseases did not follow a similar pattern. This selectivity suggests that the discovered enhancers are critical for understanding the genetic pathways underpinning immune-mediated illnesses.

Further studies showed a connection between distinct immune-mediated illnesses and individual enhancers in some unusual T cells. Eighteen immune-mediated illnesses were linked to single-nucleotide polymorphisms detected in 606 of the 63,000 bidirectional enhancers. The researchers also discovered a few target genes that are impacted by these enhancers linked to the condition. For instance, overexpression of the IL7R gene was observed with activation of an enhancer carrying a genetic variation associated with inflammatory bowel illness.

Gene expression is regulated by essential components of the genome called enhancers. The transcription of genes that regulate immune responses can be activated or enhanced in the setting of T cells via enhancers. Certain enhancers are bidirectional, utilizing both strands of DNA to generate enhancer RNA, which can then affect the expression of genes in the vicinity. Immune-mediated illnesses may result from variations in these enhancer areas that alter T cell activity. Through identification of these enhancers and comprehension of their function in gene regulation, can gain a deeper understanding of the impact that genetic differences play in immunological illnesses. With the ability to modify enhancer activity, this understanding creates new avenues for the development of targeted therapeutics that can rectify aberrant T cell functions and reduce symptoms of disease.

REFERENCE:

Oguchi, Akiko, Akari Suzuki, Shuichiro Komatsu, Hiroyuki Yoshitomi, Shruti Bhagat, Raku Son, Raoul Jean Pierre Bonnal et al. "An atlas of transcribed enhancers across helper T cell diversity for decoding human diseases." Science 385, no. 6704 (2024): eadd8394. DOI:10.1126/science.add8394

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1. COVER IMAGE: https://www.pennmedicine.org/news/news-releases/2020/december/discovery-upends-traditional-view-of-killer-t-cells-travels-in-the-body