Grant: Travel Awards - Institute Community Support

Astrocytes are among the most abundant cell types in the central nervous system (CNS) and are thought to play an important role in multiple sclerosis (MS), an autoimmune disease, in which the body's immune system attacks the protective covering around nerve cells, myelin. Our research aims to determine how astrocytes communicate with immune cells and how this affects their functions and the disease process. We focus on molecules that astrocytes produce and are part of the matrix that sits between cells (the extracellular matrix, ECM). One of these, that is present in high amounts in MS lesions, is hyaluronan. We have found that hyaluronan is important in activating immune cells and helping them get into the CNS. We therefore hypothesize that it plays an important role in the communication between astrocytes and disease-causing immune cells. On the other hand, ECM molecules are also important in immune tolerance - preventing the immune system from attacking its own body. In healthy people, this tolerance is maintained by specific regulatory immune cells, Treg. Treg depend for their survival and function on a small protein called IL-2. They cannot make IL-2 themselves and blood IL-2 levels are very low, so it's unclear how Treg access this critical factor. IL-2 can stick to a molecule named heparan sulfate (HS). HS, in turn, is attached to ECM components. We have found that Treg can make an enzyme that can cut HS molecules, heparanase (HPSE), and we think that this is the way that they access IL-2. Using a mouse model of MS, we have found that HPSE helps the function of Treg. Based on this knowledge, we have explored the possibility of "super-boosting" Treg that are engineered to suppress MS-like immune attacks, by giving them more HPSE and using these cells to treat the same mouse model. Together, our research tells us how factors in the matrix affect T cell function and how we can use this information to prevent or suppress autoimmune attacks.