The overall goal is to dissect the functional roles of the recently identified B7 family member, B7-H4, and the SLAM family member, CD48 (a CD2 ligand), in regulating organ-specific autoimmune diseases. This focus is driven by recent genetic studies of Multiple Sclerosis and murine type 1 diabetes that have implicated the genetic locus that contains these costimulatory molecules (human or mouse homologues) with disease susceptibility, together with our recent studies that point to important roles for B7-H4 and CD48 in regulating T cell activation and tolerance. To investigate the roles of B7-H4 and CD48-mediated signals in the afferent arm of the response where T cells become activated in the periphery, and in the effector arm, where potentially pathogenic T cells are driven to mediate tissue destruction, we are proposing a multifaceted approach. We will 1)investigate the role of the B7-H4 in regulating T cell tolerance and autoimmunity;2)analyze the role of CD48 in regulating the induction and effector phases of EAE;and 3)examine the roles of CD48 and B7-H4 in regulating T and B cell tolerance. We have assembled a number of novel tools that will enable us to address these important issues. To dissect the role of B7-H4 in EAE, we have developed B7-H4lg and anti-B7-H4 mAb. We also have available B7-H4-/- mice and are in the process of generating transgenic mice that inducibly express B7-H4. Our CD48-/- mice, and anti-CD48 mAb will serve as definitive tools for examining the role of CD48 during EAE. We will use MOG 35-55 specific TCR transgenic mice to visualize the effects of B7-H4 and CD48 dysregulation on the activation, migration and expansion of naive and activated T cells in vivo, and MOG 35-55 TCR x Th double transgenic mice to analyze the roles of B7-H4 and CD48 in regulating B and T cell tolerance to MOG. Taken together, these studies should lead to insights into how B7-H4 and CD48 costimulatory regulate the responses of self-reactive T cells.
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