MedUni Vienna: Breakthrough in understanding the genetic basis of immune responses

Study may accelerate development of new treatments for diseases such as cancer

A US research team with significant involvement from MedUni Vienna has analysed the molecular structures of human T cells, providing an unprecedentedly detailed description of how the immune system works. The results, which have now been published in the top journal "Nature", could help to overcome the limitations of current immunotherapies and find new approaches for the future treatment of a variety of diseases such as autoimmune diseases or cancer. Ralf Schmidt from MedUni Vienna was one of the lead authors of the study.

During their research, the scientists delved deep into the DNA of T cells. They identified certain nucleotides - the basic units of genetic information in the DNA - that influence how immune cells react to stimuli. In total, they analysed more than 100,000 such components in almost 400 genes that control essential functions of human T cells. Nucleotides serve as a code for the construction of proteins in cells. By identifying these specific DNA units, the scientists now have clarity about the exact areas in the proteins that control important immune reactions for health. The studies thus point to those areas in the immune system that could be targeted by future immunomodulating drugs.

Blueprints for new developments

"We have created amazingly precise and informative maps of DNA sequences and protein segments that control human immune responses," says study leader Alex Marson from the Gladstone Institutes in San Francisco, California. "Our mapped sites provide information about mutations that occur in patients with immune disorders. According to the research team, the enormous genetic data set can help in the development of immunotherapies against cancer, autoimmune and infectious diseases, among others. "As the study was carried out using primary T cells derived from human blood donors, the results are of great clinical relevance," emphasises Ralf Schmidt from MedUni Vienna's Clinical Institute of Laboratory Medicine, who played a key role in the study as a first author during his postdoctoral stay at the Gladstone Institutes. "This research provides deep insights into the genetic basis of immune cell function," says Schmidt. "We can now scan T cells at nucleotide resolution and create blueprints for drug development, diagnostics and other scientific endeavours."

Even more precise insights thanks to new technology

T cells play a central role in immune response and regulation, which makes them particularly interesting for scientists who want to research complex diseases such as cancer or immune disorders. Over the past ten years, CRISPR gene editing technology has been used to investigate how primary immune cells function. For this study, the team went one step further and used a newer CRISPR-based technology called base editing to make even more precise changes to hundreds to thousands of DNA sites in individual genes to paint an even more nuanced, high-resolution picture.

Publication: Nature

Base-editing mutagenesis maps alleles to tune human T cell functions;
Ralf Schmidt*#, Carl C. Ward*#, Rama Dajani, Zev Armour-Garb, Mineto Ota, Vincent Allain, Rosmely Hernandez, Madeline Layeghi, Galen Xing, Laine Goudy, Dmytro Dorovskyi1, Charlotte Wang, Yan Yi Chen, Chun Jimmie Ye, Brian R. Shy, Luke A. Gilbert, Justin Eyquem, Jonathan K. Pritchard, Stacie E. Dodgson & Alexander Marson#
DOI: 10.1038/s41586-023-06835-6
* These authors contributed equally, # Corresponding Authors

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