Scientists have partially unlocked the mystery behind T-cell identification by showing how individual T-cells determine what their functions will be.
The study “Tcf1 and Lef1 transcription factors establish CD8+ T cell identity through intrinsic HDAC activity,” was published in the journal Nature Immunology.
T-cells are crucial players in the human immune system and are responsible for an array of functions: defending the body against bacteria, viruses and parasites; involvement in antibody production; destruction of cancer cells; and generating a memory of previous infections so the body is capable of fighting them fast and efficiently in future encounters.
T-cells are themselves targets for viral infections and autoimmune diseases that can kill T-cells or severely disrupt their function, which can cause an imbalance between T-cell lineages.
Researchers at George Washington University and colleagues at the University of Iowa investigated how T-cells find their identity. Specifically studied were those that are among the two major T-cell subsets, CD4+ T-cells and CD8+ T-cells.
While CD4+ T-cells (helper T-cells) coordinate the immune response to invading infections, CD8+ T-cells (killer T -cells) actually destroy infected or tumor cells.
Understanding this mechanism is vital for future therapeutics to correct diseased-induced imbalances or depletions in T-cell repertoires.
“Many diseases operate by perturbing the balance between distinct types of T-cells,” study author Dr. Weiqun Peng, associate professor of physics at George Washington University, said in a press release. “By understanding how these cells are formed, we may, in theory, be able to manipulate T-cell creation and combat autoimmune diseases.”
The human body carries between 25 million to one billion of T-cells in the body, and both CD4+ and CD8+ T-cells are vital for a healthy immune system. A normal ratio would be about one helper cell for every four killer cells. However, in autoimmune diseases the ratio is imbalanced and often characterized by an increased number of helper T-cells. On the contrary, in viral infections the ratio is higher in CD8 T-cells.
The team discovered that a complex network of transcription factors, proteins that bind to specific DNA sequences and control gene expression, are crucial to establish individual T-cell identity.
“Think of transcription factors as switches that turn ‘on’ or ‘off’ the genes in our cells,” Peng said.
Specifically, researchers found that two specific transcription factors, Tcf1 and Lef1, switched genes on and off in a pattern that maintained the identity of CD8+ T-cells. Upon disruption of the pattern, cells became like CD4+ T-cells.
The study further revealed that transcription factors can directly influence the non-genetic state of T-cells, a previously unknown feature of the proteins.
“This significant discovery is a new perspective on gene regulation,” said fourth-year PhD student Zhouhao Zeng, one of study first authors and a research assistant in Peng’s lab.
“Obviously, CD4 and CD8 play important roles in our immune systems. If something goes wrong in the CD4/CD8 mix, our ability to fight off infections and diseases is compromised. But if biomedical scientists can develop strategies to turn on (and) off the T-cell differentiation pathway, we might be able to make drugs that hit the molecular target,” Zeng said.
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