ATP and lipoteichoic acid act cooperatively to induce a DC phenotype that promotes Th17 in an IL-23- and IL-1B-dependent manner (89.28)

Abstract

Abstract We investigated whether pairing TLR ligands with an “endogenous” danger signal, extracellular adenosine triphosphate (ATP), would act in synergy to induce in monocytes unique DC-like properties. The TLR2 ligand lipoteichoic acid (LTA) and ATP were efficient partners for cooperatively enhancing expression of IL-23 and IL-1b when monocytes were cultured in GM-CSF, but not when IL-4 was included. These cells showed DC-like properties including activated DC surface phenotype and enhanced migration towards CCR7 ligands. They also preferentially skewed allogenic CD4pos T lymphocyte responses toward the IL-22hi, IL-17hi/IFN-glo Th17 phenotype, a capacity inhibited by neutralization of either IL-23 or IL-1b, but not IL-6. Although pharmacological activation of either ionotropic or cAMP-dependent pathways acted in together with LTA to enhance IL-23, only inhibition of the cAMP-dependent pathway antagonized enhancement of cytokine production by ATP. In addition, ATP plus atypical lipopolysaccharide from P. gingivalis (signaling through TLR2) was superior to E. coli-derived LPS (TLR4 ligand) for promoting the high IL-23-secreting DC-like phenotype, but considerably inferior for inducing IL-12 p70 production when paired with IFN-g. Collectively, our data suggests TLR2 ligands encountered by innate immune cells in an environment rich in extracellular ATP can induce a distinct activation state that supports an IL-23- and IL-1b-dependent Th17 type response.