This indicates that ligation of a subset of TLRs generates proinflammatory cytokines that co-ordinate to potentiate human Th17 differentiation. In addition, the synergy between TLR-4 and TLR-7/8 in controlling the sequential production of regulatory and proinflammatory cytokines by naive CD4+ T cells was detected [78]. The observed polymorphism in DC responses to such TLR-mediated stimuli could explain differences in the susceptibility to infectious pathogens or autoimmune diseases within the human population. Furthermore, using agonists selleck chemical specific for TLR-7 (i.e. Imiquimod, Gardiquimod) or TLR-8 (ssPolyU), together with LPS, confirmed that a significant synergy in cytokine induction

is observed consistently after joint engagement of TLR-4 plus TLR-7 and/or TLR-8 [80,81]. However, the TLR-7, which is not present in DCs under normal conditions, is up-regulated dramatically in selected donors after stimulation Alvelestat by LPS, in agreement with a previous study [78,80]. Thus, the observed polymorphism between high and low DC responders is due probably to differences in TLR-7/8 up-regulation following TLR-4 stimulation, suggesting that a threshold stimulation of TLR-7 and/or TLR-8 is required to activate the joint secretion of multiple cytokines by DCs. Taken together, TLR-3, -4, -7 and -8 are required in the induction of Th17 cell differentiation and subsequent biological effects, but the role of TLR-9 is controversial,

which urgently needs to be illustrated (Fig. 3). In mice, coincidental activation of complement and several TLRs (TLR-3, -4, -7, -8 and -9) led to the synergistic production of serum factors that promote Th17 differentiation from anti-CD3/CD28 or antigen-stimulated T cells [82] (Fig. 3). Although multiple

TLR-triggered Nintedanib (BIBF 1120) cytokines were regulated by complement, Th17 cell-promoting activity in the serum was correlated with IL-6 induction, and antibody neutralization of IL-6 abrogated the complement effect [82]. These data establish a link between complement/TLR interaction and Th17 cell differentiation, and provide new insight into the mechanism of action of complement and TLR signalling in autoimmunity. Although CD4+ T cells are considered to be the major source of IL-17, especially in autoimmune diseases, recent studies have indicated that other T cell subpopulations such as CD8+ T cells, natural killer (NK) T cells and γδ T cells can also produce IL-17 [74,83]. It is reported that CCR6+ IL-17-producing γδ T cells, but not other γδ T cells, express TLR-1 and TLR-2, but not TLR-4 [84,85]. Ligands that target these pathogen recognition receptors can cause the selective expansion of IL-17+γδ T cells and functional consequences, such as neutrophil recruitment [86]. Studies have shown that γδ T cells activated by IL-1β and IL-23 are an important source of innate IL-17 and IL-21 and may act in an amplification loop for IL-17 production by Th17 cells [74,86].