Grant: Operating Grant

Interactions between white blood cells and their environment in lymphoid organs are critical for their development and function. Blood cells develop from a single stem cell in the bone marrow. In bone marrow transplantation, it is critical that these stem cells home to the bone marrow where the right environment allows them to divide, differentiate and replenish the entire immune system. Likewise, lymph nodes provide an important environment for specific mature white blood cells (T cells) to recognize infectious agents and respond appropriately. We want find out more about these environments and how they facilitate immune cell development and function. In this proposal we will examine the interaction of white blood cells with a specific component of their environment, a sticky, sugary molecule called hyaluronan (HA). HA is an essential component of the cell's environment and its interaction with its receptor, CD44, on immune cells is highly regulated. Our approach is to generate immune cells expressing mutant CD44 receptors that either cannot interact with HA or that bind HA all the time. These cells will be expressed in mice where we can observe both immune cell development and the immune response to infection. Analysis of these mice will test our hypothesis that the interaction with HA supports immune cell development in the bone marrow, enhances the production of fighter T cells and memory T cell responses. This research will provide important new knowledge that can be used to design more effective treatments for immunodeficient patients and bone marrow transplant recipients. It will be a significant step forward if we show that HA enhances fighter and memory T cell responses, as this will have important implications for the development of more effective vaccines. Vaccination is the single most effective way of preventing disease and thus saves millions of lives as well as millions in health care costs.