Modulation of regulatory T- cell function by histamine and IL-6

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The immune system is responsible for defending against infection by disease-causing microorganisms. Specialized immune cells known as mast cells and regulatory T-cells are important components of this highly evolved defence mechanism. Although usually associated with allergy, mast cells also act as sentinel cells that warn of infection. Regulatory T-cells keep immune responses under tight control in order to prevent inadvertent immune cell-mediated damage to healthy tissues. My laboratory has recently shown that histamine released as a result of mast cell activation, which typically takes place during the early stages of infection, prevents regulatory T-cells from suppressing the activation of helper T-cells, which produce an array of chemical messengers called cytokines that guide the development of immune responses. This unique effect of histamine may allow regulatory T-cell function to be temporarily suspended in order to enhance the development of protective immunity. However, the mechanism by which histamine inhibits the function of regulatory T-cells is not well understood. Using a mouse model system, we will test the hypothesis that activation of signaling pathways associated with a particular histamine receptor on regulatory T-cells interferes with the ability of these regulatory T-cells to generate an immunosuppressive molecule known as adenosine, which has previously been shown to potently inhibit immune responses by helper T-cells. In addition, we will determine whether histamine also sensitizes regulatory T cells to a cytokine known as IL-6, which is commonly produced in response to infection and may also interfere with regulatory T-cell function. Mice are a model system that is commonly used to study the molecular basis of processes that are involved in the function of the human immune system. This fundamental research will add to our knowledge of the interactions that take place between mast cells and regulatory T-cells, and may suggest important new ways to selectively enhance the development of immune responses to disease-causing microorganisms and malignancy.