B7-H4, also known as VTCN1, B7x and B7S1, is a 50-80kD glycosylated member of the BTN/MOG family of immunomodulatory protein (1, 2). Mature human B7-H4 consists of a 235aa extracellular domain (ECD) with one Ig-like V-set domain and one Ig-like C2-set domain, a 21aa transmembrane segment, and a 2aa cytoplasmic tail (3-5). Within the ECD, human B7-H4 shares 90% aa sequence identity with mouse and rat B7-H4. It shares 22%, 28% aa sequence identity with human B7-1, B7-2, B7-H1, B7-H2, B7-H3, and PD-L2. Alternate splicing of human B7-H4 generates an additional isoform that lacks the first Ig-like domain. B7-H4 is expressed on the surface of activated lymphocytes, macrophages, monocytes, dendritic cells, epithelial cells, and bone marrow- derived mesenchymal stem cells (4-8). Following binding to activated T cells, B7-H4 serves as a co-inhibitor of the T cell response. This is accomplished by reverse signaling that can induce either cell cycle arrest, or apoptosis in B7-H4 expressing cells (3-5, 9, 10). B7-H4 is up-regulated in several carcinomas in correlation with tumor progression and metastasis (2, 7, 11, 12). A soluble form of B7-H4 is elevated in the serum of ovarian cancer, renal cell carcinoma, and rheumatoid arthritis patients, also in correlation with advanced disease status (13-15). Soluble B7-H4 functions as a decoy molecule that blocks the inhibitory influence of B7-H4 on immune activation (15). Despite evidence for the involvement of B7-H4 in immune regulation, mice deficient in its expression do not show significant immune deficiencies, suggesting compensation by other molecules in vivo (16).