Abstract
In the case of epidermal barrier disruption, pathogens encounter skin-resident Langerhans cells (LCs) and are recognized by pathogen recognition receptors such as Toll-like receptors (TLRs). As the majority of microorganisms exhibit more than one TLR ligand, the mechanisms of subsequent T cell differentiation are complex and far from clear. In this study, we investigated combinatory effects on Th cell polarization by bacterial cell wall compounds peptidoglycan (PGN) and lipopolysaccharide (LPS) and by bacterial nucleic acid (DNA). Expression of maturation markers CD40, CD80, HLA-DR and CCR7 and the release of IL-1β, IL-6 and IL-23 was strongly enhanced by simultaneous exposure to PGN, LPS and DNA in LCs. As all these factors were potential Th17 driving cytokines, we investigated the potency of combinatory TLR stimuli to induce Th17 cells via LC activation. High amounts of IL-17A and IL-22, key cytokines of Th17 cells, were detected. By intracellular costaining of IL-17+T cells, IL-22− (Th17) and IL-22+ (immature Th17) cells were identified. Interestingly, one population of LPS stimulated cells skewed into IL-9+Th cells, and LPS synergized with PGN while inducing high IL-22. In conclusion, our data indicates that when mediated by a fine-tuned signal integration via LCs, bacterial TLR agonists synergize and induce Th17 differentiation.
Highlights
In the initial concept of T helper(Th) cell response, in 1986, a bias of Th1 and Th2 was proposed [1]
As all these factors were potential Th17 driving cytokines, we investigated the potency of combinatory Toll-like receptors (TLRs) stimuli to induce Th17 cells via Langerhans cells (LCs) activation
Dendritic cells (DCs) and LC-like cells were generated from human monocytes by cell culture in the presence of GM-CSF, IL-4 and TGF-β, stimulated and maturation-associated molecules were analyzed by flow cytometry
Summary
In the initial concept of T helper(Th) cell response, in 1986, a bias of Th1 and Th2 was proposed [1]. There is evidence from experimental mouse models and human studies that an increasing number of inflammatory diseases are associated with a distinct pattern of Th17 cell-specific cytokines such as IL-17, IL-23 and IL-22 [4,6,7]. Upon receiving a trigger by microbial-derived ligands such as LPS or peptidoglycan (PGN) or stimulation with toxins or irritants (danger-associated molecular pattern, DAMP), DCs and LCs release cytokines, some of which are mandatory to polarize Th-subsets [22,23,24,25]. It was preciously shown that specific strains of LPS and PGN could activate monocyte derived Langerhans cell-like cells and MUTZ-LCs that express moderate and high amounts of TLR4 and TLR2, respectively [21,26]. Our data shows graded effects of synergism with bacterial TLR ligands in inducing Th1, Th17 and Th9 cells
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