IL-18 stimulates IL-13-mediated IFN-γ-sensitive host resistance in vivo

IL-4 and IL-13 are up-regulated during in vivo responses to many nematode parasites, but increasing evidence suggests that increases in IL-13 can also occur independently of the IL-4-dominant Th2 response. Blocking B7 after Trichuris muris inoculation inhibits resistance and IL-4 elevations, instead resulting in an IFN-gamma-dominant response associated with susceptibility. However, blocking IFN-gamma under these conditions restores IL-13-dependent resistance. In this study, we examined the mechanism of IL-13 upregulation and associated protection during this in vivo immune response. CD4(+) T cells and DX5(+)TCR(-) cells were identified as the major producers of IL-13, and the DX5(+)TCR(-) cells were phenotyped as NK cells, since they expressed CD11b, IL-2R beta and Ly49C but not c-kit or Fc epsilon RI. NK cell-derived IL-13 elevations were T cell-dependent, as CD4(+) T cell depletion blocked IL-13 production by mesenteric lymph node cells and induced susceptibility. IL-13 expression was increased independently of IL-12; however, blocking IL-18 function inhibited IL-13 production and increased susceptibility. These results indicate that CD4(+) T cells and NK cells are the major sources of IL-13 during the in vivo Th1 response induced by B7 blockade and that under these conditions, IL-18 is specifically required for the in vivo up-regulation of IL-13 production and associated host protection.