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

Christopher Paustian,Min Xu,Peter A Cohen,Suyu Shu,Nancy Ramirez,Brian J Czerniecki,Kenneth S Rosenthal,Patricia Taylor,Terrence Johnson,Gary K Koski,Georg Häcker

doi:10.1371/journal.pone.0054804

Christopher Paustian, Min Xu + Show 9 more

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https://doi.org/10.1371/journal.pone.0054804

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Journal: PloS one	Publication Date: Jan 31, 2013
Citations: 25	License type: CC BY 4.0

Affiliation: University of Pennsylvania, Cleveland Clinic

Abstract

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-1β 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, CD4pos T lymphocyte responses toward the IL-22hi, IL-17hi/IFN-γlo 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-γ, 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-1β-dependent Th17 type response.

Highlights

Dendritic cells (DC) are the most potent known antigenpresenting cells and are primarily responsible for sensitizing naıve T cells to antigen
When we treated overnight cell cultures with varying concentrations of Adenosine triphosphate (ATP), activated them with S. aureus lipoteichoic acid (LTA), it was clear that the levels of IL-23 produced were much higher for the monocytes than iDC (Figure 1B)
With CD14pos monocytes, the IL-23-inducing capacity of additional Toll-like receptor (TLR) ligands (S. aureus LTA;TLR2, p[I:C];TLR3, E. coli LPS;TLR4, R848; TLR7/8) with or without added ATP

Summary

Introduction

Dendritic cells (DC) are the most potent known antigenpresenting cells and are primarily responsible for sensitizing naıve T cells to antigen. If the cytokine interleukin-12 (IL-12) is present during Th sensitization it is likely that Th1 polarization will occur, resulting in T cells that produce high levels of IFN-c and correspondingly less (or no) IL-4 and IL-5 [2]. Such cells can be highly effective for dealing with some intracellular parasites [3]. Dysregulation of these differentiation programs could result in ineffective immune responses against pathogens, debilitating autoimmune pathologies, or perhaps even promotion of carcinogenesis [14]

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