Abstract
The p53 target DD1α facilitates macrophage-mediated clearance of stress-induced apoptotic cells.
Major finding: The p53 target DD1α facilitates macrophage-mediated clearance of stress-induced apoptotic cells.
Mechanism: Homophilic interaction of DD1α expressed on dying cells and macrophages suppresses autoimmunity.
Impact: Therapeutic inhibition of DD1α may restore immune surveillance against evasive cancer cells.
Efficient clearance of apoptotic cells is critical to maintain overall tissue health, and failure to do so drives the accumulation of autoantigens that result in autoimmune disorders and developmental abnormalities. The tumor suppressor p53 has been implicated in suppressing autoimmunity, but the underlying mechanisms remain unknown. Yoon and colleagues identified the gene encoding death domain 1α (DD1α) as a p53 target gene and mediator of apoptotic cell clearance. DD1α was upregulated in response to genotoxic stress and contained a consensus p53-binding site upstream of its transcriptional start site, verifying it as a direct p53 target. Depletion or genetic ablation of DD1α resulted in deficient engulfment of apoptotic cells by macrophages. In vivo, Dd1a−/− radiosensitive organs remained larger than wild-type tissues following whole-body irradiation, supporting the hypothesis that DD1α expression is required for phagocyte-mediated engulfment and clearance of dead cells. DD1α expression on the cell surface of macrophages was also required for efficient apoptotic cell engulfment, as Dd1a−/− macrophages were deficient in clearing apoptotic thymocytes. Recombinant DD1α did not bind canonical apoptotic lipids such as phosphatidylserine. Instead, DD1α formed homophilic intercellular interactions via its immunoglobulin variable (IgV) domain; deletion of this domain resulted in impaired intercellular interaction and diminished apoptotic cell engulfment by macrophages. Dd1a−/− mice exhibited severe inflammatory disorders and autoimmune disease, providing evidence that accumulation of apoptotic cells in the absence of DD1α drives increased production of autoantigens. Furthermore, recombinant DD1α inhibited the proliferation of wild-type CD4+ and CD8+ T cells, but not Dd1a-null T cells, suggesting that DD1α suppresses T-cell activation via DD1α–DD1α interactions. These data demonstrate that homophilic DD1α interactions among dying cells, macrophages, and T cells are critical to the maintenance of healthy tissue and the regulation of autoimmunity. Moreover, they establish a model by which cancer cells with functional p53 may evade immune surveillance via upregulation of immune checkpoint inhibitors such as DD1α.