PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton

The body’s immune system recognizes and responds to foreign agents such as bacteria and viruses. Immune cells known as T cells recognize foreign substances through a protein on their surface called the T cell receptor. Specifically, the T cell receptor binds to fragments of foreign proteins displayed on the surface of other cells, which sets in motion a chain of events that leads to the T cell becoming activated. An activated T cell divides to form new cells that develop into “effector” T cells, which can mount an effective immune response. The T cell engages with the cell displaying the foreign proteins via an interface referred to as the immunological synapse. This zone of contact brings together the signaling machinery of the T cell. Like many other cells, T cells contain an internal skeleton-like structure made up of actin filaments. These filaments are crucial for the formation of the immunological synapse, in part because they help to transport the T cell receptor and other signaling proteins to the immunological synapse. Recent research suggests that a signaling protein called Notch plays an important role in instructing activated T cells to develop into effector cells. Notch is found on the surface of many cells, including T cells, and it becomes activated when it is cut by a specific enzyme. However, it was not entirely clear how T cell signaling drives the activation of the Notch protein. Britton et al. have now investigated the mechanism that leads to Notch activation in T cells from mice. The results show that a protein found inside the T cell, called PKCθ, is a major contributor to Notch activation when T cells become activated. So how does the PKCθ protein control the activation of Notch? Britton et al. observed that PKCθ inactivates a protein that normally inhibits actin filaments from forming, and does so specifically at the center of the immunological synapse. This inhibition promotes the generation of a large actin-rich structure known as the lamellal actin network. This structure is required to recruit the Notch-cutting enzyme to the immunological synapse. Further analysis revealed that Notch gets cut and activated during the first few minutes of T cell activation leading to cell division and the development of effector T cells. Following on from this work, the next challenge will be to explore if altering signaling from the T cell receptor – for example, using drugs or small molecules – can modify the activation of Notch. If so, it will be important to explore if the chemicals could potentially be used to treat diseases that develop when T cells go awry, such as rheumatoid arthritis, psoriasis and Crohn’s disease.