Grant: Project Grant

In healthy people, immune tolerance (preventing the immune system from attacking its own body) is maintained by specific regulatory immune cells, Treg. In people with autoimmune diseases such as multiple sclerosis (MS), these cells seem unable to maintain this tolerance, leaving the attack on, in the case of MS, myelin uncontrolled. Treg depend for their survival and function on a small protein called IL-2. They cannot make IL-2 themselves and levels of IL-2 in the blood are generally very low, so it's unclear how Treg access this critical factor. Like many other small proteins, IL-2 can stick to a molecule named heparan sulfate (HS). HS, in turn, is attached to structures that sit in between cells: the extracellular matrix (ECM, or "the matrix"). We have found that Treg can make an enzyme that can cut HS molecules, namely heparanase (HPSE), and we think that cutting HS in the matrix is the way that Treg access IL-2. In this project, we will determine how the interaction of IL-2 with HS affects its ability to support Treg function. In addition, using a mouse model of MS, we will investigate how HPSE helps the function of Treg. Finally, we will explore 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, this will tell us how factors in the matrix can affect Treg function and how we can use this information to make them better at suppressing autoimmune attacks.