Instead, the molecular pathway of CD47-caspase�Cindependent cell death involves Drp1 translocation from the cytosol to the mitochondria, a process controlled by chymotrypsin-like serine proteases selleckchem [25]. Once inside the mitochondria, Drp1 provokes an impairment of the mitochondrial electron transport chain, resulting in dissipation of mitochondrial transmembrane potential, reactive oxygen species generation, and a drop in ATP levels. However, a physical interaction between CD47 and the proapoptotic Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3), which is expressed upon T cell activation, inhibits BNIP3 degradation by the proteasome, thereby sensitizing T cells to apoptosis [26], [47]. At the end of the contraction phase, macrophages and neutrophils must eliminate unwanted (apoptotic or damaged) and ��unfit�� cells via phagocytosis [48].

CD47 serves as a ��don��t eat me�� signal, which inhibits cell clearance when delivered to SIRP-��+ cells [49]. Viable CD47?/? T cells are quickly eliminated from a CD47+/+, but not CD47?/? host, by SIRP-��+ cells [30], [31]. Notably, since CD47?/? mice are viable, clearance of CD47?/? cells does not occur in CD47?/? mice because these SIRP-��+ macrophages must be educated by CD47 +/+ stromal cells to acquire functional phagocytosis via interruption of the CD47/SIRP-�� pathway [50]. Nonetheless, the contraction of CD4+CD44hiCD47low T cells occurred in the immunized CD47?/? host. In fact, a CD47low status does not equate to absence of CD47. Of note, only 10% to 20% of normal CD47 expression on RBC is sufficient to prevent cell clearance [51].

Furthermore, Weissman and others demonstrated that concealing CD47 with antibodies on live cells is necessary but insufficient to trigger phagocytosis in vivo, since phagocytosis required the expression of calreticulin, which is upregulated on malignant cells [52]. In fact, the ��turning off�� of non-phagocytic signals must be coupled to the ��switching on�� of phagocytic signals to provoke cell elimination [48]. Among others, calreticulin serves as a pro-phagocytic signal, which, through binding to its macrophage counter-receptor low-density lipoprotein�Crelated protein (LRP), leads to engulfment of the target cell [28]. In the present study, calreticulin expression was not detected on viable human memory CD4 T cell subsets. In contrast, killing by 4N1K peptide induced calreticulin expression on TEM dying cells, indicating that CD47-mediated cell death represents an GSK-3 upstream event to the elimination of unwanted cells. CD47 expression/redistribution on apoptotic cells also appear to augment phagocytosis [28], [53].