T cells are the immune system’s elite fighting force, seeking out and destroying diseased cells. However, in long-term operations against chronic diseases such as viral infections and cancer, the body requires a steady supply of these killing squads. How and where these murder squads are generated is a mystery.
This prompted a team of scientists from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center (MSK) to dig deeper. They discovered that a small subset of T cells called stem T cells are responsible for generating and continually recruiting new T cells in chronic diseases. Importantly, these rare stem T cells express a protein called LEF1.
The team’s findings in a laboratory model were published on July 1. cellshowed that focusing on this LEF1-positive T cell population is key. Enhancing LEF1-positive cells overcame T-cell “exhaustion” in cases of chronic infection. and succeeded in removing them In the case of type 1 diabetes, an autoimmune disease, it suppresses overactive immune cells.
LEF1 is not specific to any particular disease and drives a fundamental mechanism by which the immune system maintains stem T cells during chronic infection, leading to autoimmune conditions. ”
Dr. Doron Bethel, Co-corresponding author, Associate Professor of Computational Biomedicine at Weill Cornell Medicine
Lead author Dr. Andrea Schittinger, a cancer immunologist at the MSK Sloan Kettering Institute, said the study could inform future cancer treatments.
“Although it was not part of this study, cancer is a chronic disease, and over time T cells lose their ability to fight cancer cells,” she said. “So that’s what we’re looking at next.”
The study was led by co-first authors Svetlana Miakicheva and Dr. Katrina Hawley, both members of the Seetinger lab at MSK, and Paul Zumbo, a senior investigator in Dr. Bethel’s lab at Weill Cornell Medicine.
Expressing LEF1 is important for stem T cells
To prove that LEF1 is not just a marker of stem cells (or “stemness”), but a central figure, the researchers used CRISPR gene editing to delete LEF1. LEF1 Genes from these rare stem T cells in mouse models.
The results were amazing. Without LEF1, stem T cells lose their viability and self-renewal ability.
In an autoimmune diabetes model, mice whose T cells lacked LEF1 were significantly protected from developing the disease because the disease-causing T cells were no longer able to maintain themselves and destroy insulin-producing cells in the pancreas.
On the other hand, it became equally clear that we were going in a different direction. When the researchers increased LEF1 levels, more stem T cells were formed and fewer cells reached the “burned out” stage, the final stage of the viral infection model.
“Our study shows that LEF1 is key to T cell stemness and persistence,” said Dr. Sittinger. “If you raise it, you get more stem cells. If you lower it, the stem cell pool disappears. Which is preferable depends on the disease context.”
Same biological strategy for different diseases
One of the most surprising discoveries came when the researchers compared stem T cells side-by-side from two diseases: autoimmune diabetes and chronic infection with a virus called lymphocytic choriomeningitis, a well-established model for studying chronic viral infections in mice.
On the surface, these conditions could not be more different. In autoimmune diabetes, T cells are highly active and aggressive and destroy healthy insulin-producing cells in the pancreas. In chronic viral infections, T cells become functionally “exhausted” and burn out over time, allowing the virus to persist.
Still, when the researchers used computational visualization techniques to map the molecular profiles of both cell types, the two stem T-cell populations clustered together as a group and became essentially indistinguishable from each other. This suggests that LEF1-induced stemness is not a disease-specific habit, but rather a common feature of how the immune system maintains itself under chronic stress. The research team found 117 genes that shared the same pattern of being turned on and off across both diseases.
“This points to a common underlying mechanism of the LEF1-driven stem T-cell state that is common to these two very different diseases,” said Dr. Bethel, whose lab performed the advanced computational analysis required for the project. “This opens up the possibility of new therapeutic strategies for a wide range of immune-related diseases.”
And how do these stem T cells maintain themselves?
The authors were surprised to discover that many of the genes and pathways used by stem T cells match those of embryonic and adult stem cells found throughout human tissues, including skin, intestine, muscle, and bone marrow.
location, location, location
Like stem cells in the intestine and bone marrow, which rely on specialized environments called “niches,” the location of immune stem cell T cells is important. Each T cell population expressed different molecular “address markers” that guided them to different locations within lymph nodes and tissues. Working with MSK physician-scientist Dr. Ivan Maillard’s lab, the authors interfered with these position signals by blocking proteins called integrins or by interfering with a pathway called Notch signaling, and surprisingly, the stem T cell pool collapsed.
“Stemness isn’t just about what’s inside the cell,” Dr. Seetinger says. “It also has to do with where the cells live and what signals they receive from the environment.”
Move findings from the bench to the bedside
For Dr. Sittinger and his colleagues, the findings also highlight the importance of conducting basic human biology research, often referred to as “basic science.” The idea is that working to understand how T cells replenish themselves may lead to new therapeutic strategies.
“We have identified what we believe to be a fundamental mechanism that the immune system widely uses to sustain itself in chronic disease,” said Dr. Sittinger. “This is the kind of discovery that could open up entirely new therapeutic directions.”
In this case, destroying stem T cells could block them from attacking an individual’s own tissues in the case of autoimmune diseases. Alternatively, in the case of viral infections or cancer, the pool of stem cell T cells could be strengthened, allowing the immune system to maintain sustained fighting power.
“Understanding how T cells maintain themselves and how their environment shapes them is fundamental to understanding cancer,” Dr. Sittinger said. “Engineering the niches and locations where cancer-fighting stem T cells can form and maintain themselves is now at the heart of our research.”
“This study demonstrates the power of multidisciplinary collaboration, where well-designed disease models, cutting-edge experiments, and advanced computational analysis are integrated to address important scientific questions,” said Dr. Bethel, who is also a member of the Englander Institute for Precision Medicine and the Sandra Edward Meyer Cancer Center at Weill Cornell Medical College.
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Reference magazines:
Miakicheva, S. Others. (2026). LEF1 and niche factors determine T cell stemness across chronic diseases. cell. DOI: 10.1016/j.cell.2026.06.022. https://www.cell.com/cell/abstract/S0092-8674(26)00709-9
