Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53

Tumor suppressor p53 linked to immune function We thought we knew all we needed to about the tumor suppressor p53. However, Yoon et al. now describe a previously unrecognized function of p53 (see the Perspective by Zitvogel and Kroemer). p53 induces expression of the gene encoding DD1α, a receptor-like transmembrane protein of the immunoglobulin superfamily. In conditions of stress, p53 activation can lead to cell death. p53-induced expression of DD1α also promotes the clearance of dead cells by promoting engulfment by macrophages. Furthermore, expression of DD1α on T cells inhibits T cell function. Thus, p53 offers protection from inflammatory disease caused by the accumulation of apoptotic cells, and its suppression of T cells might help cancer cells to escape immune detection. Science, this issue 10.1126/science.1261669; see also p. 476 p53 promotes clearance of dead cells and proper immune function. [Also see Perspective by Zitvogel and Kroemer] INTRODUCTION Programmed cell death occurs throughout life in all tissues of the body, and more than a billion cells die every day as part of normal processes. Thus, rapid and efficient clearance of cell corpses is a vital prerequisite for homeostatic maintenance of tissue health. Failure to clear dying cells can lead to the accumulation of autoantigens in tissues that foster diseases, such as chronic inflammation, autoimmunity, and developmental abnormalities. In the normal immune system, phagocytic engulfment of apoptotic cells is accompanied by induction of a certain degree of immune tolerance in order to prevent self-antigen recognition. Over the past few decades, enormous efforts have been made toward understanding various mechanisms of tumor suppressor p53–mediated apoptosis. However, the involvement of p53 in postapoptosis has yet to be addressed. RATIONALE One of the most intriguing, yet enigmatic, questions in studying homeostatic control of efficient dead cell clearance and proper immune tolerance is how these two essential activities are interrelated: The complexity of these processes is demonstrated by the many receptors and signaling pathways involved in the engulfment of apoptotic cells and stringent discrimination of self antigens from nonself antigens. Thus, there must be key connection(s) linking the balance between immune homeostasis and inflammation. In addition to the antitumor functions of p53, p53 has been implicated in immune responses and inflammatory diseases, with various roles in the immune system becoming apparent. We identified a postapoptotic target gene of p53, Death Domain1α (DD1α), that is responsive to genotoxic stresses and expressed in immune cells. DD1α appears to function as an immunoregulator of T cell tolerance. We hypothesized that p53 controls signaling-mediated phagocytosis of apoptotic cells through its target, DD1α. We determined that DD1α functions as an engulfment ligand or receptor that is involved in homophilic intermolecular interaction at intercellular junctions of apoptotic cells and macrophages. We also addressed whether DD1α deficiency caused any defects in dead cell clearance in vivo. RESULTS DD1α has similarity with several members of the immunoglobulin superfamily with the extracellular immunoglobulin V (IgV) domain, such as TIM family proteins and an immune checkpoint regulator, PD-L1. We found that the p53 induction and maintenance of DD1α expression in apoptotic cells and its subsequent functional intercellular homophilic interaction between apoptotic cells and macrophages are required for engulfment of apoptotic cells. DD1α-deficient mice showed less reduction in organ size and cell number after ionizing radiation (IR), owing to defective dead cell clearance. DD1α-null mice are viable and indistinguishable in appearance from wild-type littermates at an early age. However, at a later age, DD1α deficiency resulted in the development of autoimmune phenotypes and prominent formation of immune infiltrates in the skin, lung, and kidney, which indicated an immune dysregulation and breakdown of self-tolerance in DD1α-null mice. We demonstrated that DD1α also plays an important role as an intercellular homophilic receptor on T cells, which suggests that DD1α is a key-connecting molecule linking postapoptotic processes to immune surveillance. We found that DD1α deficiency in T cells impaired DD1α-mediated inhibitory activity of T cell proliferation. These data indicate that potential homophilic DD1α interactions are important for the DD1α-mediated T cell inhibitory role. Therefore, the results indicate a role for p53 in regulating expression of immune checkpoint regulators, including PD-1, PD-L1, and DD1α. CONCLUSION We found that the tumor suppressor p53 controls signaling-mediated phagocytosis of apoptotic cells through its target DD1α, which suggests that p53 promotes both the proapoptotic pathway and postapoptotic events. DD1α functions as an engulfment ligand that engages in homophilic intermolecular interaction at intercellular junctions of apoptotic cells and macrophages. DD1α-deficient mice showed in vivo defects in clearing dying cells that led to damage to multiple organs indicative of immune dysfunction. p53-induced expression of DD1α is a vital phase for the phagocytic engulfment process of dead cells and then facilitates the stepwise priming of immune surveillance. As a downstream target of the tumor suppressor p53, DD1α activation may extend the repertoire of p53 activities to “guardian of the immune integrity. ” p53-dependent accumulation of DD1α and its involvement in dead cell clearance and immune tolerance. DD1α functions as an engulfment ligand that participates in homophilic intermolecular interaction at intercellular junctions of apoptotic cells and phagocytes. p53 induction of DD1α is a critical step in ensuring proper clearance of cell corpses to warrant the efficient generation of precise immune responses, leading to immune tolerance. The inefficient clearance of dying cells can lead to abnormal immune responses, such as unresolved inflammation and autoimmune conditions. We show that tumor suppressor p53 controls signaling-mediated phagocytosis of apoptotic cells through its target, Death Domain1α (DD1α), which suggests that p53 promotes both the proapoptotic pathway and postapoptotic events. DD1α appears to function as an engulfment ligand or receptor that engages in homophilic intermolecular interaction at intercellular junctions of apoptotic cells and macrophages, unlike other typical scavenger receptors that recognize phosphatidylserine on the surface of dead cells. DD1α-deficient mice showed in vivo defects in clearing dying cells, which led to multiple organ damage indicative of immune dysfunction. p53-induced expression of DD1α thus prevents persistence of cell corpses and ensures efficient generation of precise immune responses.