Analysis of the CD47-SHPS-1 signaling system in autoimmune disease

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Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1), which is originally identified as a substrate for protein tyrosine phosphatases SHP-1 and SHP-2, is a member of immunoglobulin superfamily. SHPS-1 contains ITIM in its intracellular domain and its extra-cellular region interacts with CD47, which is widely expressed on immune cells. The interaction between CD47 and SHPS-1 constitutes a cell-cell communication system (the CD47-SHPS-1 signaling system) that may function in regulation of a variety of biological responses. SHPS-1 is predominantly exposed on macrophages and dendritic cells (DCs), and the CD47-SHPS-1 signaling system is considered to be a negative regulator of immune responses. We investigated the physiological roles of SHPS-1 by the use of SHPS-1 mutant mice, which lack most of the cytoplasmic region of its protein and we revealed some important functions. SHPS-1 negatively regulates the phagocytosis of RBCs by splenic macrophages and it determines both the lifespan of individual RBCs and the number of circulating erythrocytes. SHPS-1 on DCs is essential for both priming of naive T cells and the activation of NKT cells. SHPS-1 positively regulates the development of autoimmune disease and α-GalCer-induced anti-metastatic activities. These results indicate the CD47-SHPS-1 signaling system plays important roles in immune responses.