Cell death releases endogenous adjuvants that selectively enhance immune surveillance of particulate antigens

We previously reported that cells contain endogenous adjuvants in their cytoplasm that when released markedly augment the generation of CD8 T cell responses. In the present study we found that these cytosolic adjuvants similarly augmented the generation of CD4 T cell responses, and therefore must be affecting a step that is common to the generation of helper and cytotoxic T cell responses. The endogenous adjuvants work differently than a classical bacterial adjuvant, Freund's complete adjuvant. Remarkably, they stimulate the immune response to particulate and cell-associated antigens but not to the same antigens in soluble form. To gain insight into the underlying mechanisms for these effects, we studied the effect of the cytosolic adjuvants on the fate of particulate antigens and antigen-presenting cells (APC) in vivo. Injection of cytosol by itself causes no detectable change in the number or phenotype of APC in draining lymph nodes. However, co-injection of cytosol and fluorescent particles leads to the increased accumulation in the draining lymph node of dendritic cells and macrophages containing phagocytosed particles and expressing high levels of costimulatory molecules. Therefore, cell injury releases cytosolic factors that selectively enhance immune surveillance of particulate antigens released from dying cells by stimulating APC in tissues to acquire these antigens, mature and migrate to lymph nodes. This process will allow the immune system to rapidly detect and respond to viral infections and tumors.