Naïve CD8 T cells can change into different types of effector and memory CD8 T cells when the immune system responds to threats. These types help the body fight infections, respond to treatments, or sometimes cause immune-related diseases. These cells function very well when the immune response is short and intense. However, in long-lasting environments like tumors or chronic infections, these cells become less effective, a state known as T cell exhaustion.
Even though we have learned a lot about how these T cell states affect the body, it’s still unclear how these cells make their decisions and what mechanisms ensure they stay on the right path.
A team of researchers led by the Yale School of Medicine has made progress in understanding the complex interactions in the human immune system. They found a key factor that influences how T cells develop and what types they become.
To determine what causes T cells to change, researchers turned off 40 different genes in CD8 T cells, one at a time. They then observed how these cells reacted to a virus.
Destroying tumor cells using the mechanical force of T-cells
“CD8 T cells respond to signals, and we experimented with how they interpret these signals to see what type of immune cells they become,” explained Eric Fagerberg, a graduate student in Joshi’s lab.
The team discovered that a protein called Kruppel-like factor 2 (KLF2) was the only one that made T cells change unexpectedly. While it was known that KLF2 controls where T cells go in the body, they found it also acts like a switch, guiding the development of CD8 cells.
“When we turned off KLF2, we found that it caused abnormal cell states,” said Fagerberg.
The team discovered that KLF2 acts like a molecular guardrail, preventing abnormal differentiation of CD8 T cells. Silencing KLF2 made CD8 T cells take a different path, leading them away from becoming killer cells and towards a dysfunctional state called exhaustion, which reduces their ability to fight infections and control tumors.
Nikhil Joshi, PhD, associate professor of immunology at YSM, compared this to a car switching from a highway to a country road. We want CD8 cells to take the efficient highway and become effective killers for infections or tumors. However, in cancer, CD8 cells take an offramp and end up on country roads, making them less effective. KLF2 is unique because it keeps CD8 cells on the highway, preventing them from taking the offramp.
Joshi said, “By understanding the molecular mechanisms that control the fate of immune cells, we can begin to use them to regulate how the immune system functions.”
This work won’t immediately create new treatments for infections or diseases, but it helps researchers better understand the immune system. Now, they have a clearer idea of how to make T cells stay strong and avoid becoming exhausted, making therapies more effective in the future.
Journal Reference:
- Eric Fagerberg, John Attanasio et al. KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection. Science. DOI: 10.1126/science.adn2337
