Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity

Alum has long been used as a vaccine adjuvant, yet the mechanisms by which it increases antigen-specific immune responses remain unclear. Flach et al . now report that alum interacts with lipids in the plasma membrane of dendritic cells, resulting in nonphagocytic uptake of antigen and increased association with CD4 + T cells. These results suggest that, at least for dendritic cells, lipids rather than proteins may sense alum and trigger downstream signaling events that lead to enhanced T cell responses. As an approved vaccine adjuvant for use in humans, alum has vast health implications, but, as it is a crystal, questions remain regarding its mechanism. Furthermore, little is known about the target cells, receptors, and signaling pathways engaged by alum. Here we report that, independent of inflammasome and membrane proteins, alum binds dendritic cell (DC) plasma membrane lipids with substantial force. Subsequent lipid sorting activates an abortive phagocytic response that leads to antigen uptake. Such activated DCs, without further association with alum, show high affinity and stable binding with CD4 + T cells via the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function–associated antigen-1 (LFA-1). We propose that alum triggers DC responses by altering membrane lipid structures. This study therefore suggests an unexpected mechanism for how this crystalline structure interacts with the immune system and how the DC plasma membrane may behave as a general sensor for solid structures.