IL-33-activated dendritic cells induce an atypical T_H2-type response

Background: IL-33, a recently discovered IL-1 family cytokine, is implicated in the development of T_H2-type responses in vivo. However, the cellular targets for IL-33 are poorly understood. Objective: We tested the hypotheses that dendritic cells (DCs) respond to IL-33 and that IL-33-activated DCs prime naive CD4⁺ T cells to produce T_H2-type cytokines. Methods: Dendritic cells were derived from mouse bone marrow, and their expression of the IL-33 receptor, ST2, was examined by fluorescence-activated cell sorting and real-time RT-PCR. The DCs' responses to IL-33 were examined by fluorescence-activated cell sorting (MHC-II and CD86 expression) and by ELISA (IL-6 and IL-12 production). The ability of IL-33-activated DCs to prime naive T cells was assessed by coculture with isolated CD4⁺ T cells and by measuring cytokines in the supernatants. Results: ST2 mRNA was detectable in highly purified DCs. ST2 protein was abundant within DCs, but was barely detectable on their cell surfaces. Incubation of DCs with IL-33 increased their expression of MHC-II and CD86 and production of IL-6, but IL-12 was not produced. Anti-ST2 antibody inhibited IL-6 production from IL-33-activated DCs by approximately 60%; anti-ST2 did not affect IL-6 production from LPS-activated DCs. When incubated with naive CD4⁺ T cells alone, IL-33 failed to stimulate cytokine production. In contrast, naive CD4⁺ T cells incubated with IL-33-activated DCs showed robust production of IL-5 and IL-13, but IL-4 and IFN-γ were undetectable. Conclusion: Dendritic cells respond directly to IL-33 through ST2. The IL-33 and DC interaction may represent a new pathway to initiate T_H2-type immune responses.