MEMBRANE ANCHORING AND FUNCTION OF CD16

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The knowledge of the structure and function of Fc receptors is fundamental in understanding the defense of the immune system. In humans, the structure and binding properties of three types of IgG Fc receptors (Fc-gamma-Rs) have been described. Of these Fc-gamma-yRIII (CD16) has demonstrated to be physiologically important. CD16, is a glycoprotein of 50-70 kD and is expressed on neutrophils, natural killer (NK) cells, eosinophils and tissue macrophages. In vivo studies using CD16 monoclonal antibodies have demonstrated that CD16 plays a major role In clearing immune complexes from the circulation. CD16 has two distinct membrane anchors; phosphatidylinositol glycan (PIG) in neutrophils and a polypeptide in NK cells. CD16 is deficiently expressed in PNH, an acquired hematopoietic stem cell disease which affect the expression of PIG-anchored proteins. The proposed research uses CD16 negative PNH neutrophils to test whether the defect in CD16 expression leads to abnormal neutrophil functions by comparing the Fc dependent functions of normal and PNH neutrophils before and after reconstituting CD16 expression. The functional ability of polypeptide-anchored CD16 expression on NK cells will also be compared under the same conditions. These studies will delineate the consequences of CD16 deficiency on neutrophils and the influence of membrane anchor on the function of CD16. This proposal is also focused on establishing stable transfectants expressing/secreting various forms of CD16. Since no cell lines that express CD16 are available, the stable transfectants will be an excellent tool for further structure/function studies. The various forms of CD16 will be purified from large scale cultures of these stable transfectants and biochemically and functionally characterized. The functionally characterized purified molecule can be used to define the role of these receptors in cellular functions. In the future, a purified CD16 may directly be used therapeutically to treat diseases such as chronic immune thrombocytopenic purpura and prevent Fc mediated HIV and other viral infections. Alternatively, complete knowledge of its structure and function may be useful in designing therapeutic agent for treatment of these diseases.