T cells are an elite fighting force of the immune system, seeking out and destroying diseased cells. But in a prolonged campaign against a chronic condition—such as a viral infection or cancer—the body needs a steady supply of these killer troops. Where and how these armies of killers are created has been a mystery.
That led a team of scientists from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center (MSK) to dig deeper. They found that a small subset of T cells, called T stem cells, are responsible for generating new T cells and for their continued replenishment in chronic diseases. Importantly, these rare T stem cells express a protein called LEF1.
The team’s findings in laboratory models, published July 1 Cellshowed that targeting this population of LEF1-positive T cells is key. Enhancement of LEF1-positive cells exceeded T cell “exhaustion” in the case of chronic infection. And their removal was successful reining in overactive immune cells in the case of type 1 diabetes, an autoimmune disease.
LEF1 drives a fundamental mechanism by which the immune system maintains T stem cells during chronic infection, as well as driving autoimmune conditions, rather than being unique to a particular disease.”
Dr. Doron Betel, co-corresponding author, associate professor of computational biomedicine in medicine, Weill Cornell Medicine
The research also has the potential to inform future cancer treatments, said senior author Dr. Andrea Schietinger, a cancer immunologist at MSK’s Sloan Kettering Institute.
“Although it was not part of this study, cancer is a chronic disease where T cells lose their ability to fight cancer cells over time,” he said. “So that’s what we’re looking at next.”
The study was led by first authors Svetlana Miakicheva and Dr. Katrina Hawley, members of the Schietinger Lab at MSK, and Paul Zumbo, senior scientist in the lab of Dr. Betel at Weill Cornell Medicine.
Expression of LEF1 is critical for T stem cells
To demonstrate that LEF1 was not just a stem (or “stem”) marker, but a central player, the researchers used CRISPR gene editing to delete the LEF1 gene from these rare T stem cells in their mouse models.
The results were impressive. Without LEF1, T stem cells lost their ability to persist and self-renew.
In the autoimmune diabetes model, mice whose T cells lacked LEF1 were significantly protected from developing the disease because the disease-causing T cells could no longer maintain and destroy insulin-producing cells in the pancreas.
Meanwhile, going the other way proved just as revealing. When the researchers increased the levels of LEF1, more T-stem cells were formed and fewer cells reached the terminal, “burnt-out” stage in the viral infection model.
“Our study shows that LEF1 is key to the generation and persistence of T cells,” said Dr. Schietinger. “Increase it and you have more stem cells. Take it away and the stem cell pool disappears. Which one is desirable depends on the context of the disease.”
Different diseases, same biological book
One of the most surprising findings came when the team compared T stem cells from the two diseases side-by-side: autoimmune diabetes and chronic infection with a virus called lymphocytic choriomeningitis—an established model for studying chronic viral infection in mice.
On the surface, these circumstances could not be more different. In autoimmune diabetes, T cells are highly active and aggressive – destroying healthy insulin-producing cells in the pancreas. In chronic viral infection, T cells become functionally “exhausted,” burning out over time and allowing the virus to persist.
And yet, when the researchers mapped the molecular profiles of both types of cells using a computer visualization technique, the two populations of T stem cells came together as a single group—essentially indistinguishable from each other. This suggests that LEF1-driven strain is not a quirk associated with disease, but rather a common feature of how the immune system maintains itself under chronic stress. The team found 117 genes in both diseases that share the same pattern of being turned on or off.
“This points to a common underlying T cell state mechanism, driven by LEF1, that is common to these two very different diseases,” said Dr. Betel, whose laboratory performed the sophisticated computational analyzes required for the project. “This opens up the possibility of new therapeutic strategies for a wide range of immune-related conditions.”
And how are these T stem cells maintained?
The authors were surprised to find that many genes and pathways used by T stem cells match those of embryonic and adult stem cells, which are found in all our tissues, including skin, gut, muscle and bone marrow.
Location, location, location
Similar to gut or bone marrow stem cells—which depend on specialized environments called “niches”—the location of immune T stem cells matters. Each population of T cells expressed different molecular “target tags” that direct them to distinct locations within lymph nodes and tissues. In collaboration with the laboratory of MSK doctor-scientist Dr. Ivan Maillard, the authors disrupted these localization signals—either by blocking proteins called integrins or by interfering with a pathway called Notch signaling—and remarkably, the T stem cell pool collapsed.
“The corona is not just about what’s inside the cell,” said Dr. Schietinger. “It’s also where the cell lives and the signals it receives from its environment.”
Moving findings from bench to bedside
For Dr. Schietinger and her colleagues, the findings also underscore the importance of research in fundamental human biology, which is often called “basic science.” The idea is that by working to understand how T cells are replenished, new therapeutic strategies may emerge.
“We have identified what we believe is a fundamental mechanism, a mechanism that the immune system uses broadly to sustain itself in chronic disease,” Dr. Schietinger said. “This is the kind of finding that can open up completely new directions for treatment.”
In this case, disrupting the T stem cells could potentially prevent them from attacking a person’s tissues in the case of autoimmune disorders. Or, alternatively, in the case of viral infections — or cancer — the pool of T stem cells could be boosted, helping the immune system maintain a resilient fighting force.
“Understanding how T cells maintain themselves—and how their environment shapes them—is fundamental to understanding cancer,” said Dr. Schietinger. “The engineering sites and sites where cancer-fighting T cells can be formed and maintained are the focus of our research now.”
“This work demonstrates the power of interdisciplinary collaboration where well-designed disease models, cutting-edge experiments, and advanced computational analysis combine to address important scientific questions,” said Dr. Betel, who is also a member of the Englander Institute for Precision Medicine and the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
