IL-33–activated dendritic cells induce an atypical T H2-type response

Abstract

IL-33, a recently discovered IL-1 family cytokine, is implicated in the development of T(H)2-type responses in vivo. However, the cellular targets for IL-33 are poorly understood. 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(H)2-type cytokines. 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. 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-gamma were undetectable. Dendritic cells respond directly to IL-33 through ST2. The IL-33 and DC interaction may represent a new pathway to initiate T(H)2-type immune responses.