Czerniecki, Brian J.

Abstract Stimulation of dendritic cells (DCs) by exogenous danger signals such as single Toll-like receptor (TLR) ligands results in generalized DC activation. Recently, Napolitani and co-workers showed select TLR ligand pairings induced a more specialized DC activation program including enhanced IL-12 p70 secretion and the capacity to polarize CD4 T cells into IFN-γ-secreting Th1 cells. We therefore examined the effect of pairing an exogenous TLR2 ligand (lipoteichoic acid) with an endogenous danger signal, ATP, which is found in high extracellular concentrations in damaged tissues, malignant tumors, and possibly other pathophysiological settings. ATP added to LTA modified somewhat the expression of common DC activation markers, but primarily induced a distinct pattern of cytokines with greatly enhanced levels of both IL-23 and IL-1β, while TNF, IL-10 and IL-6 remained mostly unchanged. IL-12 was not produced. These DC induced a Th17 response when stimulating allogeneic T cells in a manner partially dependent on IL-1β. These studies show that pairing of endogenous and exogenous danger signals can induce a specialized DC activation program that may have important physiological implications.