Essential and synergistic roles of IL1 and IL6 in human Th17 differentiation directed by TLR ligand-activated dendritic cells

Requirements for human Th17 differentiation in the context of activated dendritic cells (DCs) are still emerging. Here, we demonstrate that several Toll-like receptor (TLR) ligands, particularly LPS and a synthetic lipoprotein, activate human DCs to direct increased human Th17 differentiation. Based on neutralization studies, IL1, IL6, and TGFbeta contributed to human Th17 differentiation induced by LPS-activated DCs. Furthermore, TLR ligand-activated DCs produced high levels of IL6 and low levels of IL1beta. In an antigen presenting cell (APC)-free system, the minimum requirements identified for human Th17 differentiation from adult naive CD4(+) T cells, depleted of CD25(+) cells, were TGFbeta and high levels of IL1beta. However, in the presence of the physiologically low levels of IL1 such as those produced by DCs, both TGFbeta and IL6 were also essential. These results help to explain the conflicting reports in the literature on the roles of IL1 and IL6 on human Th17 differentiation.