Extracellular ATP and Toll-Like Receptor 2 Agonists Trigger in Human Monocytes an Activation Program That Favors T Helper 17

Extracellular ATP and Toll-Like Receptor 2 Agonists Trigger in Human Monocytes an Activation Program That Favors T Helper 17

Paustian C; Taylor P; Johnson T; Xu M; Ramirez N; Rosenthal K S; Shu S Y; Cohen P A; Czerniecki B J; Koski G K

PLOS ONE

2013

2013-01

Strategically-paired Toll-like receptor (TLR) ligands induce a unique dendritic cell (DC) phenotype that polarizes Th1 responses. We therefore investigated pairing single TLR ligands with a non TLR-mediated danger signal to cooperatively induce distinct DC properties from cultured human monocytes. Adenosine triphosphate (ATP) and the TLR2 ligand lipoteichoic acid (LTA) selectively and synergistically induced expression of IL-23 and IL-1 beta from cultured monocytes as determined by ELISA assays. Flow cytometric analysis revealed that a sizable sub-population of treated cells acquired DC-like properties including activated surface phenotype with trans-well assays showing enhanced migration towards CCR7 ligands. Such activated cells also preferentially deviated, in an IL-23 and IL-1-dependent manner, CD4(pos) T lymphocyte responses toward the IL-22(hi), IL-17(hi)/IFN-gamma(lo) Th17 phenotype in standard in vitro allogeneic sensitization assays. Although pharmacological activation of either ionotropic or cAMP-dependent pathways acted in synergy with LTA to enhance IL-23, only inhibition of the cAMP-dependent pathway antagonized ATP-enhanced cytokine production. ATP plus atypical lipopolysaccharide from P. gingivalis (signaling through TLR2) was slightly superior to E. coli-derived LPS (TLR4 ligand) for inducing the high IL-23-secreting DC-like phenotype, but greatly inferior for inducing IL-12 p70 production when paired with IFN-gamma, a distinction reflected in activated DCs' ability to deviate lymphocytes toward Th1. Collectively, our data suggest TLR2 ligands encountered by innate immune cells in an environment with physiologically-relevant levels of extracellular ATP can induce a distinct activation state favoring IL-23- and IL-1 beta-dependent Th17 type response.

adaptive immunity; calcium ionophore; cd14(+) monocytes; cells; growth-factor-beta; host-defense; human dendritic cells; il-12 production; in-vivo; Science & Technology - Other Topics; serum-free conditions; th17

Journal Article

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