Researchers will use cellular imaging in mice to see how two proteins, which are essential for the early stages of immune T cell development, then degrade before they inhibit the T cells’ further growth and maturation. Understanding this normal degradation process may provide important insight into how failure of these proteins to degrade at the proper time can lead to malfunctioning T cells that attack the body’s own tissues.
Immune T cells learn to recognize and attack specific invaders. Occasionally, during T cell development, they learn incorrectly. They mistake the body’s own tissues as foreign and attack them, producing autoimmune diseases. In the early stages of T cell development, two proteins—PU.1 and E2A—are essential. These two proteins, whose actions are tightly controlled, must then completely disappear at later stages of T cell development. Otherwise, for instance, PU.1 will block T-cell maturation, which will result in immune deficiency. The researchers hypothesize that the two proteins clear out through a process of metabolic degradation called “ubiquitination.” Improper regulation of the degradation of either protein, according to the researchers’ hypothesis, alters T cell development and causes autoimmune diseases such as arthritis and juvenile diabetes.
The researchers aim to determine the molecular process of PU.1 and E2A degradation during T cell development by using cellular imaging to visualize the process in mice. They will image the two proteins at different stages of T cell development, using “ubiquitin-mediated fluorescence complementation” in single living cells. By revealing the PU.1 and E2A degradation process that promotes late stage T cell development, the investigators can identify molecular targets for drugs that might prevent malfunctions in this process that produce autoimmune diseases.
Significance: This study of metabolic processes that are critical for normal immune T cell development may lead to development of new types of therapies to treat T cell malfunctions that produce autoimmune diseases.