We recently reported that polyclonal anti-CD3 epsilon-pulsed Th2 cells mediate local tissue inflammation (DTH2) when injected into naive syngenic recipient mice, and that this response is entirely dependent on IL-4 in BALB/c (H-2d) mice. We now describe a different cytokine dependence in mice that bear a H-2b MHC haplotype. Injection of either soluble IL-4R (sIL-4R) or anti-TNF Ab partially inhibited swelling that was mediated by Th2 cells from high TNF-producing C57BL/6 mice. Anti-TNF and sIL-4R in combination were required to completely abrogate the swelling reaction and cellular infiltrate. Adoptive transfers across strain barriers showed that the TNF dependence was dictated by the origin of the transferred cells, rather than by the recipient. Experiments with intra-H-2 recombinant C57BL/10 strains indicated that TNF released by Th2 cells was correlated with the involvement of TNF in DTH2: Th2 cells from the H-2Db strains C57BL/10 and B10.A(2R) produced high amounts of bioactive TNF and mediated swelling that was partially inhibited by anti-TNF. In contrast, Th2 cells from B10.D2 and B10.A mice (H-2Dd) produced low levels of TNF, and anti-TNF had no effect on DTH2 in these strains. Our results suggest a linkage between the TNF dependence of DTH2, the capacity of Th2 cells to release TNF upon restimulation, and the donor H-2D haplotype; strain-dependent allelic expression of TNF seems to determine the involvement of this cytokine in DTH2.