Uncategorized Friday, 2024/12/20
Cells in the immune system do not always fight. They often rest and wait for threats such as viruses or bacteria. When these threats arise, these cells activate to protect the body. The delicate balance between rest and activation is crucial for human health—immune cells must be prepared to activate to resist threats, but if they become too active, it may lead to autoimmune diseases. But what controls this important balance?
In a new study, researchers from institutions such as the Gladstone Institute and the University of California, San Francisco focused on T cells, which play a crucial role in the immune system. They identified how a network composed of different proteins controls T cell rest and activation. The relevant research results were published online in the journal Nature, with the title “Central control of dynamic gene circuits governs T cell rest and activation”.
Notably, they found a protein called MED12 that plays a central role in coordinating when T cells rest or activate. When they removed MED12 from T cells, these cells were neither fully activated nor fully rested.
Dr. Alex Marson, the corresponding author of the paper, said, “We found that MED12 is a key switch that keeps quiescent T cells quiescent and activated T cells active. By controlling other key genes that regulate rest and activation, this protein can coordinate multiple functions of T cells.”
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This discovery has provided scientists with a better understanding of the fundamental biology of T cells and paved the way for the development of new therapies for various diseases primarily involving T cell function.
Dr. Jonathan Pritchard, co-author of the paper and professor of genetics and biology at Stanford University, said, “This new understanding of how to control T cell rest and activation may ultimately have an impact on the treatment of cancer or autoimmune diseases.”
These authors focused on two closely related T cells: classical T cells and regulatory T cells. The former can help protect the body from infection and cancer invasion, while the latter can suppress unnecessary immune responses and prevent autoimmune reactions that occur when the human immune system mistakenly attacks healthy cells.
Maya Arce, the first author of the paper and a graduate student in Marson’s laboratory, said, “Although these T cells have opposite roles in the immune system, they typically rely on the same environmental signals to tell them when to activate. We want to understand the mechanisms that allow different cell types to produce different responses, despite their similarities.”
For this purpose, the author studied a protein called IL2RA, which is abundant on the surface of activated T cells. They want to see how the level of this protein changes with the activation or deactivation of various genes. They systematically tested thousands of genes using CRISPR genome editing technology and observed how they altered IL2RA levels in classical and regulatory T cells. Protein MED12 stands out among them.
“Surprisingly, this same protein regulates the function of T cells differently in both resting and activated states,” Arce said.
In resting classical T cells, MED12 promotes rest and helps maintain low levels of IL2RA. However in regulatory T cells and activated classical T cells, the authors found that MED12 has the opposite effect and helps to increase the level of IL2RA.
In order to better understand the functionality of MED12, the Marson team collaborated with Dr. Nevan Krogan, Senior Researcher at the Gladstone Institute, and Dr. Ansuman Satpathy, Associate Researcher. They confirmed together that MED12 binds to a large number of proteins known to control chromatin structure, which is the packaging form of intracellular DNA. Next, they found that MED12 and its related proteins bind to different positions in the genome under different T cell types and states.
Satpathy said, “We found that by altering the chromatin structure or DNA assembly in different regions of the genome, MED12 and its related proteins can control which genes are most easily activated under different conditions.”
When the author removed MED12 from T cells, these chromatin changes decreased, and the resting and activated states of classical T cells were not very apparent.
Krogan said, “Clearly, MED12 sits at the top of a hierarchical structure, much like an orchestra conductor controlling the functions of other genes and proteins. Without MED12, the boundary between rest and activation becomes blurred. Resting T cells appear more active, while activated T cells look more like resting T cells.”
In some cases, this inhibitory effect may be beneficial. The author found that classical T cells lacking MED12 are less likely to undergo cell death under high-level stimulation after activation, as this cell death process typically reduces the effectiveness of cancer immunotherapy. These results help explain why another recent study suggests that engineered T cells lacking MED12 may be more effective in targeting tumors (Science, 2022, doi: 10.1126/science. abn5647).
Marson said, “Our research provides a deeper understanding of the important role of MED12 and helps explain how T cells coordinate their different functions. A deeper understanding of this mechanism can ultimately help us design more effective immunotherapy.”
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Reference
Maya M. Arce et al. Central control of dynamic gene circuits governs T cell rest and activation. Nature, 2024, doi:10.1038/s41586-024-08314-y.