Researchers at Dana-Farber/Boston Children’s: Differences in wiring of “exhausted” and effective T cells indicate possible gene-editing targets
Reporter: Aviva Lev-Ari, PhD, RN
“Exhausted T cells display a variety of functional defects,” says Nicholas Haining, MD, of Dana-Farber/Boston Children’s, senior author of the new paper. “They are paralyzed and don’t have the fire-power to destroy cancer or virally-infected cells. For us, the question in this study was, do exhausted cells represent a distinct type of T cell or are they merely a ‘groggy’ version of functional T cells?”
With chronically infected mice as their model, the researchers used a new technology called ATAC-seq to map the regulatory regions of the genome – the sections of DNA involved in switching genes on and off – in the animals’ exhausted and functional CD8+ T cells. (CD8+ T cells are programmed to identify and eliminate cancerous and infected cells.)
“We found the landscape of regulatory regions to be fundamentally different in exhausted and functional T cells,” Haining says. “There were thousands of instances where a regulatory region appeared in exhausted T cells but not in their functional counterparts, and vice versa. This tells us that the two types of cells use very different wiring diagrams to control their gene activity.”
The researchers then tested whether removing a regulatory stretch of DNA that spurs the production of PD-1 would drive down expression of the protein. Using CRISPR/Cas9 technology, they snipped out that region and indeed, PD-1 expression dropped.