Myeloid responders to programmed cell death

Abstract

Abstract Necroptosis is a programmed form of cell death that more efficiently primes CD8 T cell responses when compared to apoptosis. This efficiency has been associated with key signaling effects downstream of RIP kinase activation. However, mechanisms whereby these cell-intrinsic signals translate into enhanced adaptive immunity remain unclear. We hypothesized that dying cells would attract and engage with distinct myeloid populations based on which cell death pathway is active, and that these interactions would determine T cell priming ability. By introducing dying cells loaded with non-degradable ‘antigen’ into naïve mice, we have tracked myeloid cells that interacted with necroptotic or apoptotic cell debris up to 72 hrs after injection, corresponding to early detectable differences in T cell priming. Migratory dendritic cells equivalently took up antigen following either necroptosis or apoptosis. However, necroptosis resulted in a greater number of antigen positive macrophages and lymph node resident dendritic cells. Understanding how the immune system recognizes and responds to distinct forms of cell death will benefit investigations into cytotoxic and immunotherapeutic drug combinations.