Press Releases
New Genomic Screens Illuminate How Genetic Variants Drive Autoimmune Disease Through T Cells
In an article published today in the journal Nature Genetics, Benaroya Research Institute (BRI) scientists, led by John Ray, PhD, unveil how genetic variants associated with autoimmune diseases directly alter T cell gene regulation and function. Dr. Ching-Huang Ho, a staff scientist in Dr. Ray’s lab and first author of the study, developed and deployed a comprehensive suite of cutting-edge genomic tools in human CD4 T cells to determine how autoimmune disease-associated genetic variants influence T cell activity. Their study identified new pathways and potential therapeutic targets for diseases such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes, and inflammatory bowel disease.
CD4 T cells are crucial for regulating immune responses. However, it remains unclear which genetic differences cause these cells to allow an attack on healthy tissue in the context of autoimmune disease. Traditionally, researchers try to uncover these mechanisms by conducting functional studies in immortalized cancer cell lines, which may not accurately represent the genetic integrity and diversity of human immune cells. Complicating matters further, the vast majority of these genetic variants fall in “non-coding” regions of DNA that don’t make proteins but still play key roles in regulating genes. In this study, BRI researchers performed high-throughput functional studies in primary CD4 T cells that come directly from human donors, offering a more accurate view of how genetic variants affect primary human T cell function in autoimmunity.
The authors tested more than 18,000 genetic variants with a possible link to autoimmunity using a high-throughput genomic tool called massively parallel reporter assay (MPRA), which can measure how genetic variants affect gene activity. They identified 545 variants that likely affect genetic expression within CD4 T cells, called expression-modulating variants (emVars). Compared to emVars from immortalized cell lines, they saw that primary CD4 T cell emVars were more specific to inflammation and T cell activation. This highlights the value of testing these assays in primary cells and suggests that genetic networks related to T cell activation are important in determining autoimmune risk. To validate these findings, the authors used epigenome-editing with CRISPR-interference (CRISPRi) to test whether these emVars are within genomic regions that alter T cell function and found that many of them affect T cell proliferation, providing direct evidence that these genetic risk regions influence the immune pathways likely involved in autoimmunity.
“These primary CD4 T cell emVars serve as a great jumping-off point for in-depth functional studies to identify genes that cause multiple autoimmune diseases. This brings us a step closer to understanding the mechanisms underlying autoimmune diseases and finding therapeutic targets,” said Dr. Ray. This project was also supported by several crucial collaborations outside of BRI with the laboratories of Dr. Ryan Tewhey at the Jackson Laboratory in Bar Harbor, Maine, Dr. Carl de Boer at the University of British Columbia, Dr. Michael Guo at the University of Pennsylvania, and Dr. Jay Shendure at the University of Washington.
For more information about BRI, visit www.benaroyaresearch.org.