Macrophage WDFY3 mitigates autoimmunity by enhancing efferocytosis and suppressing T cell activation in mice

Efficient efferocytosis is crucial for immune homeostasis. Conversely, excessive apoptotic cell (AC) death and impaired macrophage efferocytosis lead to autoantigen release, autoantibody production, and immune activation. It is unclear whether immunogenic autoantigens from impaired clearance are the sole cause of autoimmunity or if AC efferocytosis directly alters macrophage function, affecting T cell activation and amplifying autoimmunity. Our prior work identified WDFY3 as essential for macrophage efferocytosis. Here, we demonstrate that myeloid Wdfy3 knockout exacerbates autoimmunity in young mice receiving systemic AC injections and middle-aged mice developing autoreactivity. Mechanistically, myeloid Wdfy3 deletion impairs efferocytosis, increasing autoantigen availability, and augments MHC-II-mediated antigen presentation and cytokine dysregulation, thereby promoting CD4+ T cell activation. In contrast, WDFY3 overexpression enhances efferocytosis, suppresses macrophage-mediated CD4+ T cell activation, and mitigates autoimmunity. Thus, macrophage WDFY3 functions as a protective factor against autoimmunity. Enhancing macrophage efferocytosis and reprogramming macrophage responses to ACs may represent promising strategies to limit autoimmune disorders and age-associated autoimmunity. Excessive apoptotic cell death and defective efferocytosis drive loss of tolerance and autoimmunity; however, a direct role for macrophage-specific defects in autoimmunity is underexplored. Here, the authors identify macrophage WDFY3 as a negative regulator of autoimmunity by enhancing efferocytosis and reducing MHC-II-mediated antigen presentation, T cell activation, and cytokine dysregulation.