CD47/IAP Modulation of Immune Cell Functions

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DESCRIPTION (provided by applicant): As a result of work during the first cycle of this grant, we realize that CD47 or integrin-associated protein can modulate the function of a number of vascular integrins through its direct activation of heterotrimeric Gi. Much less is known about CD47 function in the immune system. We have found that CD47 and its counter receptor SIRPalpha constitute a novel recognition of self system that prevents phagocytosis of CD47-bearing circulating cells. Failure of this system leads to autoimmune syndromes. All ligands of CD47 (thrombospondin, monoclonal antibodies and SIRPalpha can induce a novel form of cell death in activated lymphocytes, i.e., Jurkats and anti-CD3 activated normal T cells. The mechanism involves heterotrimeric G proteins and attenuation of PKA activity leading to a loss of delta-psi-m. We find that CD47 null mice have a severe defect in IgM to IgG class switching. Here we propose to investigate the mechanisms behind these newly revealed functions of CD47 in the immune system. The aims are: 1. Determine the biological role and mechanism of the CD47-SIRPalpha inhibition of phagocytosis of circulating cells. This normally attenuates presentation of self antigens and its mechanism suggests a novel treatment for autoimmune hemolytic anemia. 2. Investigate the mechanism of CD47 mediated cell death, particularly the connection from G proteins to mitochondrial damage. 3. Use CD47 null mice to define the role of CD47 in development of immune cells, in class switching during an immune response and in autoimmunity.