Role and mechanism of negative costimulatory pathways in EAE

Brigham And Women'S Hospital, Boston MA

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Abstract

EAE is an inflammatory disease of the central nervous system initiated by myelin antigen-specific encephalitogenic CD4+ Th1 cells. After encountering antigen, T cells receive signal 1 through the TCR and signal 2 through "positive" costimulatory molecules leading to full activation. Other costimulatory molecules such as CTLA4 provide a negative signal (co-inhibitory) for T cell activation and may be important for terminating immune responses. Recently, other pathways that provides negative signaling to T cells has been described, the PD1-PDL1/2 pathway, and the B7-H3 and B7-H4 pathways. The main goal of this proposal is to explore the immune regulatory mechanisms of PDL1/PDL2 and the B7H3 and B7H4 in regulating EAE. We have unique reagents (monoclonal antibodies and fusion proteins) and animal models (gene knockout and TCR transgenic animals) that will enable us to dissect the role of this pathway in a clinically relevant disease model. We will use these tools to study the following: Aim 1: Immune regulatory mechanisms of PDL1 and PDL2. We will investigate the hypothesis that PDL1 and PDL2 provide specific signals to various T cell lineages, as well as to effector versus memory cells. We will investigate the hypothesis that expression of PDL1 or PDL2 in the central nervous system (CNS) is protective and the therapeutic potential of this pathway as to whether it could cooperate with costimulatory signal blockade. Aim 2: Immune regulatory mechanisms of B7-H3 and B7-H4 and the importance of their parenchymal expression. Our hypothesis is that B7-H3 and B7-H4 pathways play an important role in regulating EAE via expression on CNS parenchymal cells and APCs. We will examine the function of these pathways in Th1, Th2 and Th17 cells as well as in effector versus memory T cells. We will also examine the therapeutic potential of this pathway as to whether it could cooperate with blocking positive cosimulatory signals.