The ubiquitously expressed cell surface glycoprotein CD47 on host cells can inhibit phagocytosis of unopsonized or opsonized viable host target cells. Here we studied the role of target cell CD47 in macrophage uptake of viable or apoptotic murine thymocytes. As expected, IgG-opsonized viable CD47(-/-) thymocytes were taken up more efficiently than equally opsonized Wt thymocytes. However IgG-opsonized apoptotic thymocytes from Wt and CD47(-/-) mice were taken up equally. Although uptake of apoptotic thymocytes by non-activated bone marrow-derived macrophages was phosphaticlylserine (PS)-independent, while uptake by non-activated resident peritoneal macrophages was PS-dependent, both macrophage populations showed I reduced uptake of non-opsonized apoptotic CD47(-/-) thymocytes, as compared with the uptake of apoptotic Wt thymocytes. This difference was only seen with non-activated macrophages, and not with beta-1,3-glucan-activated macrophages. CD47 promoted binding of thymocytes to macrophages, which did not require F-actin polymerization. CD47 became clustered on apoptotic thymocytes, both colocalized with or separated from, Clustered PS and cholesterol-rich GM-1 domains. Thus, CD47 does not inhibit, but rather Support, both PS-independent and PS-depenclent uptake of apoptotic cells in the murine system. This mechanism only comes into play in non-activated macrophages. (C) 2009 Elsevier Inc. All rights reserved.