RUI: Differential Phosphorylation of Nur77 In Immature and Mature T Cells

Haverford College, Haverford PA

Investigators

Abstract

T lymphocytes (T cells) regulate a body's defense against infection and recognize pathogens through receptors on their surfaces (T cell receptors) that bind to minced pieces of proteins (peptides) from viruses, bacteria, or other invaders. New T cells are produced every day in an organ called the thymus, and every new T cell produced expresses a novel T cell receptor. Because these novel T cell receptors cannot intrinsically discriminate between proteins made by an invading pathogen and proteins made by the body's own cells, autoimmunity is a constant threat for an organism. However, the body has ways to destroy autoreactive T cells as they browse the thymus during their development in the thymus. Specifically, if an immature T cell binds strongly to any thymic peptide it encounters, its T cell receptor will generate signals that induce the cell to die. An immature T cell that does not bind to a self-peptide strongly is permitted to mature into a functional T cell and exit from the thymus. At this point a mature T cell responds to strong T cell receptor signals not by dying, but by dividing and initiating an immune response. The molecular switch(es) responsible for this marked change in interpretation of a strong T cell receptor signal between an immature and mature T cell are not known, yet are the basis for our understanding of how organisms protect themselves against autoimmunity. This project is designed to improve our understanding of the differences in response to T cell receptor stimulation and builds upon findings that a protein that regulates cell death, known as Nur77, is treated differently in mature versus immature T cells. Whereas both cell types respond to T cell receptor signals by increasing production of Nur77, only the mature T cells respond additionally by altering the protein through the attachment of phosphate molecules (phosphorylation). Investigators will determine what internal signals are responsible for these alterations and how and why they differ between the two cells. They will also work to understand the impact of phosphorylation on the function of Nur77 and have specifically hypothesized that the changes disable Nur77, preventing it from turning on a set of genes that coordinate the cell death program. This work will clarify our understanding of how a T cell population that is screened against responsiveness to 'self' proteins develops the ability to respond to pathogens it encounters outside the thymus. The PI has a strong mentoring program in undergraduate laboratory research. Her students co-author papers and present their findings at meetings.