T cells are positioned at the frontline of the body’s immune system to fight infection, cancer, and autoimmune disease. While different subtypes of T cells exist, how these cells take their different forms has remained elusive.

Now, a multi-institutional team of researchers led by Yale School of Medicine (YSM) has added clarity to the complex, dynamic molecular interactions that occur in the human immune system. In a new study, the researchers have identified one of the levers that controls the fate of T cells and what subtype they transform into. Their findings were published recently in the journal Science.

“Researchers often think of T cells as falling into different buckets—T cells for infection or T cells for cancer or autoimmunity,” said Nikhil Joshi, PhD, associate professor of immunology at YSM and senior author of the study. “We want to have a more holistic view of this process. T cells all start at the same place, and we wanted to understand the rules that control how T cells change in response to the molecular signals they see as they mount a defense.”

The lever that determines immune cell fate

One type of T cell—known as a CD8—is constantly on the prowl in the human body in search of intruders that can cause infections and disease. CD8 T cells transform, or differentiate, at different stages of the immune response. During the normal process, these cells can become either activated killers that destroy infected cells or memory cells that contain the recipe to relaunch a defense against future infections. But they can also slip into dysfunctional, or “exhausted,” states that make them less effective in an immune response.

To home in on what triggers the differentiation in these T cells, Joshi and his colleagues silenced 40 genes in CD8 T cells, one at a time. They then examined how the cells fared when faced with a virus.

“CD8 T cells respond to signals, and we played around with how they interpret these signals to see what flavor of immune cells would result,” said Eric Fagerberg, a graduate student in the Joshi lab and first author on the paper.

The research team found that a protein called Kruppel-like factor 2 (KLF2) was the only one they tested that pushed the T cells along an unexpected path. It was known that KLF2 controlled where the cells go in the body, but the team found KLF2 also acted like a lever, regulating the differentiation of CD8 cells.

“When we knocked out KLF2, we found that it produced an aberrant collection of cell states,” said Fagerberg.

The team identified that KLF2 acts like a molecular guardrail that prevents this abnormal CD8 T cell differentiation. Silencing KLF2 drove the CD8 T cells along a different path, directing them away from becoming killer cells and toward a dysfunctional state called exhaustion that reduces the cells’ effectiveness at fighting infection and controlling tumor progression.

Joshi likened the findings to a car switching its route from a highway to a country road. In infection or tumors, we would want the CD8 cells to follow the efficient, straightforward superhighway to become effective killers. But in cancer, CD8 cells take an offramp and end up on country roads, making them less impactful in their fight against cancer. KLF2 is unique because it is required for CD8 cells to both ignore the offramp and keep driving down the highway.

Clarifying rules opens new approaches for research

While this work will not directly lead to new treatments for infection or disease, it will provide researchers with a better understanding of the rules that the immune system follows. Researchers now have a clearer idea of which levers to pull to make more effective choices when approaching therapeutic options that prevent T cells from following the exhausted route and push them to keep up the good fight.

“By understanding the molecular mechanisms that control the fate of immune cells, we can begin to use them as a tool to regulate how the immune system functions,” said Joshi.

The research reported in this news article was supported by the National Institutes of Health (awards P30CA016359 and S10OD026996). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The research also received support from the Pershing Square Sohn Foundation and the Lung Cancer Research Foundation.