CD47/IAP Modulation of Immune Cell Functions

描述（由申请人提供）：在本资助第一个周期的工作中，我们意识到CD47或整合素相关蛋白可以通过直接激活异三聚体Gi来调节许多血管整合素的功能。人们对CD47在免疫系统中的功能知之甚少。我们发现CD47及其对抗受体SIRPalpha构成了一种新的自我识别系统，可以阻止携带CD47的循环细胞的吞噬。这个系统的失败会导致自身免疫综合征。CD47（血小板反应蛋白）、单克隆抗体和SIRPalpha的所有配体都可以在活化淋巴细胞中诱导一种新的细胞死亡形式，即Jurkats和抗cd3活化的正常T细胞。其机制涉及异三聚体G蛋白和PKA活性的衰减，导致δ -psi-m的丢失。我们发现CD47缺失小鼠在IgM到IgG类转换方面存在严重缺陷。在这里，我们建议研究CD47在免疫系统中这些新发现的功能背后的机制。目标是：1。确定CD47-SIRPalpha抑制循环细胞吞噬的生物学作用和机制。这通常会减弱自身抗原的呈现，其机制提示了一种治疗自身免疫性溶血性贫血的新方法。2. 研究CD47介导细胞死亡的机制，特别是G蛋白与线粒体损伤的联系。3. 利用CD47缺失小鼠来确定CD47在免疫细胞发育、免疫反应中的类转换和自身免疫中的作用。

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.