title: Acute myeloid leukaemia-derived Langerhans-like cells enhance Th1 polarization upon TLR2 engagement.
abstract: Langerhans cells (LCs) represent a highly specialized subset of epidermal dendritic cells (DCs), yet not fully understood in their function of balancing skin immunity. Here, we investigated in vitro generated Langerhans-like cells obtained from the human acute myeloid leukaemia cell line MUTZ-3 (MUTZ-LCs) to study TLR- and cytokine-dependent activation of epidermal DCs. MUTZ-LCs revealed high TLR2 expression and responded robustly to TLR2 engagement, confirmed by increased CD83, CD86, PD-L1 and IDO expression, upregulated IL-6, IL-12p40 and IL-23p19 mRNA levels IL-8 release. TLR2 activation reduced CCR6 and elevated CCR7 mRNA expression and induced migration of MUTZ-LCs towards CCL21. Similar results were obtained by stimulation with pro-inflammatory cytokines TNF-α and IL-1β whereas ligands of TLR3 and TLR4 failed to induce a fully mature phenotype. Despite limited cytokine gene expression and production for TLR2-activated MUTZ-LCs, co-culture with naive CD4(+) T cells led to significantly increased IFN-γ and IL-22 levels indicating Th1 differentiation independent of IL-12. TLR2-mediated effects were blocked by the putative TLR2/1 antagonist CU-CPT22, however, no selectivity for either TLR2/1 or TLR2/6 was observed. Computer-aided docking studies confirmed non-selective binding of the TLR2 antagonist. Taken together, our results indicate a critical role for TLR2 signalling in MUTZ-LCs considering the leukemic origin of the generated Langerhans-like cells.
authors.affiliation: Institute of Pharmacy (Pharmacology and Toxicology), Freie Universität Berlin, D-14195 Berlin, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bock
authors.affiliation: Institute of Pharmacy (Pharmaceutical Chemistry), Freie Universität Berlin, D-14195 Berlin, Germany.
authors.forename: Manuela S
authors.initials: MS
authors.lastname: Murgueitio
authors.affiliation: Institute of Pharmacy (Pharmaceutical Chemistry), Freie Universität Berlin, D-14195 Berlin, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.affiliation: Institute of Pharmacy (Pharmacology and Toxicology), Freie Universität Berlin, D-14195 Berlin, Germany. Electronic address: Guenther.Weindl@fu-berlin.de.
authors.forename: Günther
authors.initials: G
authors.lastname: Weindl
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D006801:Humans; D007801:Langerhans Cells / Q000166:cytology / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology*; D008213:Lymphocyte Activation; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology*
chemical_list: D016207:Cytokines; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2
keywords: Acute myeloid leukaemia (AML); Langerhans cells; Pro-inflammatory cytokines; T helper type 1 (Th1) cells; TLR2; Toll-like receptors (TLR)