Scientists from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center published findings on July 1, 2026, in the journal Cell, identifying the protein LEF1 as a key factor in the persistence of stem T cells during chronic diseases. Stem T cells are a subset of T cells responsible for continuously replenishing T cells in chronic disease.

Researchers determined that stem T cells express LEF1. In laboratory models, increasing LEF1-positive cells addressed T cell exhaustion during chronic infection. Conversely, removing LEF1-positive cells reduced overactive immune cells in cases of type 1 diabetes. Investigators used CRISPR gene editing to remove the LEF1 gene from stem T cells in mouse models. Stem T cells without LEF1 lost their ability to persist and self-renew in these models. Mice whose T cells lacked LEF1 were protected from developing autoimmune diabetes in laboratory models. When LEF1 levels were increased, more stem T cells formed, and fewer cells reached the terminal stage in viral infection models.

Doron Betel, an associate professor of computational biomedicine in medicine, stated, "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." The scientists compared stem T cells from mouse models of autoimmune diabetes and chronic lymphocytic choriomeningitis virus infection. The molecular profiles of these stem T cells clustered together, indicating a shared state. The team identified 117 genes with the same on or off pattern across both diseases. Betel noted, "This points to a common underlying mechanism of stem T cell state, driven by LEF1, that is shared across these two very different diseases."

Additionally, researchers investigated the role of cell location signals. They disrupted these signals by blocking integrins or interfering with Notch signaling, which resulted in the collapse of the stem T cell pool in laboratory models. The study was led by co-first authors Svetlana Miakicheva, Dr. Katrina Hawley, and Paul Zumbo.