Characterisation of an âeat-meâ signal on dying and HIV-1-infected T cells

The clearance of dying cells by phagocytes, termed efferocytosis, is regulated by a combination of âeat-meâ and âdonât eat-meâ signals expressed on the dying cell surface. Efferocytosis is essential for ontogeny and tissue homeostasis, but can also mediate the spread of pathogen infection, and its dysregulation leads to inflammatory disorders. The Sattentau laboratory recently reported that the macrophage efferocytic uptake of HIV-1-infected CD4+ T cells drives efficient infection of macrophages. However, the signals involved in the macrophage capture of the infected T cell remain undefined, but cell death appears to be an important component of this recognition. In this study a novel efferocytic pathway which is based on the cleavage of the heavily sialylated glycoprotein CD43 acting as a potent âdonât eat-meâ signal for macrophages is investigated. Data presented in this thesis imply that; i) CD43 shedding is mediated by ADAM10 which is activated by T cell death, and ii) cleavage of CD43 as a donât eat-me signal from the surface of dying and infected T cells triggers their engulfment by macrophages. In the context of HIV-1infection, interventions in this pathway may have the potential of reducing targeted macrophage infection. Also, the knowledge of this novel efferocytic pathway has general implications for understanding and potentially treating unwanted inflammatory disorders.