The objectives of this grant in the next funding period will be to analyze the immunoregulatory properties of placental protein 14 (PP14) in greater depth and to design and evaluate PP14 derivatives with immunotherapeutic potential. This competitive renewal application builds upon a body of work from our laboratory during the prior funding period that first demonstrated a direct PP14 inhibitory effect on T cells, established PP14's unique "rheostatic" mechanism of action in elevating T cell receptor activation thresholds, developed the first recombinant derivatives of PP14, defined PP14's molecular binding potentials, and cloned and characterized animal PP14 homologues. Based upon our novel insights into PP14's functional properties, we now hypothesize that PP14 may explain some immunological phenomoena of pregnancy, such as the shift towards Th2 cytokine output and the clinical improvement documented in pregnant women suffering from certain autoimmune diseases. With this in mind, we intend to move towards PP14-based immunotherapeutics for inhibiting pathogenic T cells. The specific aims are: 1) to define the phenotype and fate of lymphocytes inhibited by PP14; 2) to elucidate the molecular mechanisms of PP14-mediated T cell inhibition, with the goal of identifying critical membrane receptor(s) and intracellular cell signaling pathway(s) influenced by PP14; and 3) to design recombinant derivatives of PP14 with enhanced functions, and to explore their therapeutic use in autoimmune and alloimmune animal disease models. The proposed studies combine basic and applied features.