LEF1 Identified as Master Regulator of Stem T Cells, Opening New Therapeutic Avenues Across Chronic Diseases
Key Insights
Scientists from MSK and Weill Cornell Medicine discovered that LEF1 (search)-expressing stem T cells are responsible for sustaining T cell populations in chronic diseases, published July 1 in Cell.
CRISPR deletion of LEF1 (search) eliminated stem T cell persistence and protected mice from autoimmune diabetes, while boosting LEF1 overcame T cell exhaustion in chronic viral infection.
Molecular profiling revealed that stem T cells from autoimmune diabetes and chronic infection are nearly indistinguishable, sharing 117 genes and a common LEF1 (search)-driven mechanism.
A team of scientists from Memorial Sloan Kettering Cancer Center (MSK) and Weill Cornell Medicine has uncovered a fundamental mechanism by which the immune system sustains its T cell arsenal during chronic disease. Their findings, published July 1 in Cell, identify the transcription factor LEF1 (search) as a master regulator of rare "stem T cells" — a small subset of T cells responsible for continuously replenishing killer T cells in conditions ranging from chronic viral infection to autoimmune diabetes.
The discovery points to a shared biological playbook underlying T cell persistence across vastly different diseases, opening the door to novel therapeutic strategies that could either boost or suppress these stem-like cells depending on the clinical context.
LEF1 (search): More Than a Marker of Stemness
While LEF1 (search) had previously been observed on a subset of T cells, its functional role remained unclear. To demonstrate that LEF1 is not merely a marker but a central driver of T cell stemness, the researchers used CRISPR gene editing to delete the LEF1 gene from stem T cells in mouse models.
The results were definitive. Without LEF1 (search), stem T cells lost their ability to persist and self-renew. In a model of autoimmune diabetes, mice whose T cells lacked LEF1 were significantly protected from developing the disease — the pathogenic T cells could no longer sustain themselves and destroy insulin-producing cells in the pancreas.
Conversely, when the team boosted LEF1 (search) levels in a chronic viral infection model, more stem T cells formed and fewer cells progressed to the terminal, functionally "burned out" stage.
"Our study shows that LEF1 (search) is key to T cell stemness and persistence," said senior author Dr. Andrea Schietinger, a cancer immunologist in MSK's Sloan Kettering Institute. "Turn it up, and you get more stem cells. Remove it, and the stem cell pool disappears. Which of those is desirable depends on the disease context."
A Shared Mechanism Across Divergent Diseases
One of the study's most striking findings emerged when the researchers compared stem T cells from two seemingly opposite conditions: autoimmune diabetes, where T cells are hyperactive and destroy healthy tissue, and chronic infection with lymphocytic choriomeningitis virus, where T cells become exhausted and allow the virus to persist.
Using computational visualization techniques, the team mapped the molecular profiles of both cell types and found that the two stem T cell populations clustered together as a single, essentially indistinguishable group. The analysis identified 117 genes across both diseases that share the same pattern of being switched on or off.
"This points to a common underlying mechanism of stem T cell state, driven by LEF1 (search), that is shared across these two very different diseases," said co-corresponding author Dr. Doron Betel, associate professor of computational biomedicine in medicine at Weill Cornell Medicine. "LEF1 drives a fundamental mechanism by which the immune system sustains stem T cells during chronic infection, as well as drives autoimmune conditions, rather than being unique to a particular disease. This opens the possibility to new therapeutic strategies for a broad range of immune related conditions."
The authors were also surprised to find that many genes and pathways employed by stem T cells matched those of embryonic and adult stem cells found in tissues including skin, intestine, muscle, and bone marrow.
The Stem Cell Niche: Location Is Everything
Beyond intrinsic cellular programming, the study revealed that the environment surrounding stem T cells is critical to their survival. Each T cell population expressed distinct molecular "address labels" that directed them to specific locations within lymph nodes and tissues — analogous to the specialized niches required by stem cells in the gut or bone marrow.
In collaboration with the lab of MSK physician-scientist Dr. Ivan Maillard, the researchers disrupted these location signals by blocking integrin proteins or interfering with the Notch signaling pathway. In both cases, the stem T cell pool collapsed.
"Stemness isn't just about what's inside the cell," Dr. Schietinger said. "It's also about where the cell lives and what signals it receives from its environment."
From Bench to Bedside: Therapeutic Implications
The findings carry significant implications for multiple disease areas. In autoimmune disorders, disrupting stem T cells could potentially prevent them from attacking an individual's own tissues. In chronic viral infections or cancer, boosting the stem T cell pool could help the immune system maintain a durable fighting force.
Although cancer was not part of this study, Dr. Schietinger noted that "cancer is a chronic disease where T cells lose their capacity to fight cancer cells over time. So that's what we're looking at next."
The work aligns with MSK's broader Marie-Josée and Henry R. Kravis Cancer Ecosystems Project, which investigates how cancer cells communicate with immune cells and surrounding tissues to support tumor growth. "Understanding how T cells sustain themselves — and how their environment shapes them — is fundamental to understanding cancer," Dr. Schietinger said. "Engineering niches and locations where cancer-fighting stem T cells can form and maintain themselves is at the heart of our research now."
The study was led by co-first authors Svetlana Miakicheva and Dr. Katrina Hawley of the Schietinger Lab at MSK, along with Paul Zumbo of Dr. Betel's lab at Weill Cornell Medicine. The research was supported by the National Institutes of Health, the Breakthrough T1D foundation, the Cancer Research Institute, and other funding sources. The authors declared no competing interests.