Scientists previously believed that the mechanism of T cell regeneration varied from disease to disease, but a new study published in the journal Cell has turned this concept upside down.
A research team from Weill Cornell and Sloan Kettering Cancer Center discovered that stem T cells in autoimmune diabetes and chronic viral infections are almost identical at the molecular level and share a single mechanism driven by the LEF1 protein, meaning that one treatment could work for multiple diseases.
T cells play a crucial role in eliminating viruses, bacteria, and cancer cells, but their numbers and effectiveness are depleted in chronic diseases. The research team discovered that a small subset of these cells, called stem cells and carrying the LEF1 protein, are responsible for continuously replenishing these forces.
Using CRISPR technology, they deleted the LEF1 gene from these cells in mice, so they completely lost their ability to survive and regenerate, and the mice became protected from autoimmune diabetes.
When they boosted LEF1 levels, more stem cells formed and there was less fatigue in viral infections, proving that LEF1 is the actual key to the survival of these cells.
The biggest surprise came when the team compared stem cells from two completely different diseases: autoimmune diabetes and chronic viral infection.
Despite the differing behavior of the cells, ranging from aggressive to fatigued, molecular analyses revealed that stem cells from both diseases were nearly identical, sharing 117 genes that function in the same way. This confirms the existence of a common underlying mechanism, driven by LEF1, operating in different diseases. Researchers also discovered that T stem cells utilize the same biological pathways as embryonic and adult stem cells in tissues, and that their location within the body plays a crucial role in their survival.
To confirm the role of the surrounding environment, the researchers disrupted the signals that guide stem T cells to their locations within the lymph nodes. They did this by either blocking proteins called integrins or by disrupting a cell communication pathway known as the Notch pathway. Once these signals were disrupted, the stem cell supply was completely depleted, demonstrating that the survival of these cells depends not only on their internal components but also on the signals they receive from their surrounding environment.
This discovery opens up promising therapeutic prospects in two directions: in autoimmune diseases, disabling stem cells can prevent them from attacking tissues, while in chronic infections and cancer, boosting them can help the immune system maintain a permanent striking force.
Lead author Dr. Andrea Schettinger confirms that her team is currently working on engineering suitable environments in which these cells can form and persist, a step that is reshaping our understanding of the immune system and opening up promising prospects for innovative treatments in autoimmunity, cancer, and viral infections.
