Modulation of T lymphocyte Activation by ß2-Adrenergic Receptor Signalling Pathways

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Background: My research program is focused on studying the regulation of helper T cells in the adaptive immune system. Helper T cells detect infections and coordinate the immune system response against infections. T cells have to be regulated by the body, otherwise they can accidentally attack self-tissue leading to autoimmunity, or, if they fail to function properly, opportunistic infections could occur. My laboratory studies the basic question of how adrenaline hormones regulate helper T cells. Adrenaline is constantly rising and falling in the body, but we do not yet understand how this affects the adaptive immune system. In the proposed research we will expand the basic knowledge of how helper T cells respond to adrenaline receptors. In objective (1) we will characterize how stimulating the adrenaline receptor affects helper T cell signalling pathways, and determine how this alters the function of helper T cells. In objective (2) we will develop a new protocol to measure changes in gene expression, and use this to determine how the adrenaline receptors alter the function of helper T cells. In objective (3) we will test a novel idea about how adrenaline receptors alter the way helper T cells use carbohydrates for energy. Methods: For the proposed research, we will get helper T cells from healthy human volunteers who donate a small amount of blood. The cells are then kept alive in the laboratory where we will create an immune response and test the effects of various chemicals that stimulate adrenaline receptors. We will measure signalling pathways, genes and proteins, and carbohydrates using a variety of cytometry, microscopy, and molecular biology techniques. Relevance: We have discovered that some chemicals boost helper T cells, while other chemicals inhibit helper T cells. Understanding more about how this works will help immunologists improve their models describing the immune system. Another way to apply the fundamental knowledge that we create is in the understanding of how behaviour alters the immune system. For example, stress is known to suppress immunity against viruses, but stress can also cause flare-ups in autoimmunity. We speculate that if an autoimmune patient gets stressed their adrenaline goes up, which may boost helper T cells making their symptoms worse. Pharmaceutical and biotechnology companies will be interested in this knowledge to develop new drugs to treat autoimmune diseases, and patients may better understand their symptoms. Future directions: Our long term objectives are to study these novel signalling pathways in helper T cells, which can be quite diverse and mediate many cellular responses. Another long term goal is to test our theories by stimulating natural adrenaline responses in humans and measuring their immune responses. We will also collaborate with other research groups in order to apply our basic knowledge to help discover better ways to treat people with autoimmunity or immune-deficiencies.