The TCF-1 protein allows different parts of otherwise isolated DNA segments to intertwine in a way that is necessary for the development of T cells — an important element of the body’s immune system — and the role of TCF-1. This protein’s role in making T cells can give rise to new cells, according to a new study by researchers at the University of Pennsylvania’s Perelman School of Medicine, shedding light on possible immunotherapy treatments. The findings are published in Natural Immunology.
Mammalian DNA is folded in a 3D structure creating what one might consider different neighborhoods in the genome. These neighborhoods formally known as topological binding domains, or TADs, are sections of DNA that are isolated from other neighborhoods to control the expression of different genes. Sometimes, these neighborhoods need to intercalate because a piece of DNA in one vicinity may be required to control and develop a unique set of genes in another.
By studying the mechanism of the TCF-1 protein and how it reconfigures the genome, a team led by Golnaz Vahedi, PhDAn associate professor of Genetics and a member of the Penn Institute of Immunology and the Penn Institute of Genetics, discovered that the TCF-1 protein has a unique ability to induce plasticity in cells. in neighboring regions during T-cell development.
“These regions, or isolated neighborhoods, are like stickers for social distancing,” says Vahedi. “Basically, they say, ‘Stay away — keep a certain distance.’ But what this protein does is remove these patches and say, ‘Now you can actually mix together.’ It disrupts spatial distance.”
Using various basic science experiments, the researchers found that TCF-1, along with the CTCF protein, targets the boundaries of insulating neighborhoods when the T cell is developing, thus weakens the insulation and minimizes the distance between previously blocked neighborhoods. The co-association of TCF-1 with CTCF increases the interaction between neighboring regions as T cells mature, suggesting that TCF-1 plays an essential role in T cell development and maturation, is a central component of immunotherapy to manipulate T cells to make drugs to proliferate and kill cancer cells.
“Immune checkpoint inhibitors revive T cells to attack cancer cells. High levels of the TCF-1 protein correspond to T-cell expansion and favorable outcomes after immune checkpoint blockade, Vahedi said. “However, it remains a mystery about the unique expression of TCF-1 in this therapeutic strategy. If we understand in detail, this protein and the other players in the process — the complex of structural proteins that work together with TCF-1 to make this splicing happen — the subsequent manipulations of The machinery that occurs in immune checkpoint blockade can hopefully make this intervention even more effective or effective. “
Source: University of Pennsylvania
