This application seeks support for elucidating the role ofthe SLAMF receptors in the pathogenesis of Systemic Lupus Erythematosus (SLE) with the ultimate goal to develop SLAMF-based therapeutic strategies that can be applied to SLE patients. Because of the outcomes of our studies with cells derived from SLE patients and our exciting findings with genetically altered mice, which develop lupus-related autoimmunity, we now have the systems in place to dissect how cell interaction mechanisms and signaling initiated by the SLAMF receptors contribute to the control of tolerance to autoantigens and to the pathogenesis of human SLE. These insights and tools are the basis for a Program Project application entitled: