Human immunity is an incredibly complex system that has to be very carefully regulated by the body. We need our immune systems to be able to leap into action when our health is threatened by pathogens or cancerous cells, and when the immune response goes awry, serious disease and death can result. Scientists have now created a detailed map of immune function using cutting-edge CRISPR tools that edit individual letters in genes, one at a time, in T cells. The findings have been reported in Nature.
In this study, the researchers focused on about 400 genes that relate to immune function in T cells, which are a crucial type of white blood cell that are an essential part of the body's defenses. The investigators analyzed over 100,000 places in the genomes of functional T cells. By zeroing in on very specific parts of genes, the researchers aimed to reveal the most critical parts of the proteins that are related to immunity. This could help scientists develop better drugs that modulate the immune system or find drug targets for a variety of autoimmune diseases or types of cancer.
"We've created astoundingly precise and informative maps of DNA sequences and protein sites that tune actual human immune responses," said study leader Alex Marson, MD, PhD, director of the Gladstone-UCSF Institute of Genomic Immunology, among other appointments.
"Our mapped sites provide insights into mutations found in patients with immune disorders. The enormous genetic dataset also works as a sort of cheat sheet, explaining biochemical code that will help us program future immunotherapies for cancer, autoimmunity, infections, and beyond."
Human T cells were used in this study, and CRISPR base editing was applied to those cells to make very specific changes to their DNA. Instead of deleting or dowregulating an entire gene or large portion of a gene, base editing alters one base of a gene at a time. This enables researchers to take a very fine-tuned approach, and identify the exact part of a gene that is especially relevant to some aspect of physiology. In this case, T cells have a major role in the activation and control of the immune response.
"This study is zooming into the genetic basis of immune cell functions," added co-first study author Ralf Schmidt, MD, who is now a medical fellow at the Medical University of Vienna. "We can now interrogate T cells at nucleotide resolution, generating blueprints for drug development, diagnostics, and further scientific endeavors."
Sources: Gladstone Institutes, Nature
