Cytokine-Dependent Modification of IL-12p70 and IL-23 Balance in Dendritic Cells by Ligand Activation of Vα24 Invariant NKT Cells

Abstract

CD1d-restricted invariant NKT (iNKT) cells play crucial roles in various types of immune responses, including autoimmune diseases, infectious diseases and tumor surveillance. The mechanisms underlying their adjuvant functions are well understood. Nevertheless, although IL-4 and IL-10 production characterize iNKT cells able to prevent or ameliorate some autoimmune diseases and inflammatory conditions, the precise mechanisms by which iNKT cells exert immune regulatory function remain elusive. This study demonstrates that the activation of human iNKT cells by their specific ligand α-galactosylceramide enhances IL-12p70 while inhibiting the IL-23 production by monocyte-derived dendritic cells, and in turn down-regulating the IL-17 production by memory CD4+ Th cells. The ability of the iNKT cells to regulate the differential production of IL-12p70/IL-23 is mainly mediated by a remarkable hallmark of their function to produce both Th1 and Th2 cytokines. In particular, the down-regulation of IL-23 is markedly associated with a production of IL-4 and IL-10 from iNKT cells. Moreover, Th2 cytokines, such as IL-4 and IL-13 play a crucial role in defining the biased production of IL-12p70/IL-23 by enhancement of IL-12p70 in synergy with IFN-γ, whereas inhibition of the IFN-γ-promoted IL-23 production. Collectively, the results suggest that iNKT cells modify the IL-12p70/IL-23 balance to enhance the IL-12p70-induced cell-mediated immunity and suppress the IL-23-dependent inflammatory pathologies. These results may account for the long-appreciated contrasting beneficial and adverse consequence of ligand activation of iNKT cells.

A pivotal role for antigen-presenting cells overexpressing SOCS3 in controlling invariant NKT cell responses during collagen-induced arthritis

“…Interestingly, ligand activation of iNKT cells by DCs results in upregulation of CD40 ligand expression on the iNKT cells, which subsequently can stimulate DC maturation and IL-12 production 41–43. Furthermore, a recent study by Uemura et al showed that ligand-activated iNKT cells modify the IL-12p70/IL-23 balance in DCs mainly via the production of both Th1 and Th2 cytokines 44. This suggests that suboptimal stimulatory signals and soluble factors from α-GalCer-activated iNKT cells (eg, IL-2, IFNγ and/or IL-4) can have a reciprocal stimulatory effect on the APCs in our co-culture system, which in turn can be inhibited in the SOCS3-transduced APCs.…”

Immunotherapeutic strategies targeting natural killer T cell responses in cancer

“…IL-12p70 is involved in the induction and amplification of the Th1 response, while IL-23 mediates inflammatory responses, through induction of expansion of Th17 cells (Ortaldo et al 2004). Uemura et al demonstrated that when NKT cells are co-cultured with DCs, NKT cells enhance the IL-12p70 production while downregulating IL-23 production by DCs (Uemura et al 2009). …”

Bisphenol A in combination with TNF-α selectively induces Th2 cell-promoting dendritic cells in vitro with an estrogen-like activity

“…This finding is supported by the previous observation that other factors such as ligands for Toll-like receptors are required for DC-mediated differentiation of IL-17-producing Th cells. [46][47][48] Whether Th polarization is also modified by BPA/Toll-like receptor-stimulated DCs remains to be determined.…”