Tumor Necrosis Factor α Is a Critical Component of Interleukin 13–Mediated Protective T Helper Cell Type 2 Responses during Helminth Infection

In vivo manipulation of cytokine and/or cytokine receptor expression has previously shown that resistance to infection with the caecum-dwelling helminth Trichuris muris is dependent on interleukin (IL)-4 and IL-13 while susceptibility is associated with a T helper cell type 1 (Th1) cytokine response. Using gene-targeted mice deficient in tumor necrosis factor (TNF) receptor signaling and anti–TNF-α monoclonal antibody treatment, we have extended these studies to reveal a critical role for TNF-α in regulation of Th2 cytokine–mediated host protection. In vivo blockade of TNF-α in normally resistant mice, although not altering IL-4, IL-5, or IL-13 production in the draining lymph node, significantly delayed worm expulsion for the duration of treatment. IL-13–mediated worm expulsion in IL-4 knockout (KO) mice was also shown to be TNF-α dependent, and could be enhanced by administration of recombinant TNF-α. Furthermore, TNF receptor KO mice failed to expel T. muris, producing high levels of parasite-specific immunoglobulin G2a and the generation of a predominantly Th1 response, suggesting that the absence of TNF function from the onset of infection dramatically alters the phenotype of