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 up-regulation 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-2Rbeta and Ly49C but not c-kit or Fc epsilonRI. 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.