IL-4 receptor α chain (IL-4Rα)-deficient mice were generated by gene-targeting in BALB/c embryonic stem cells. Mutant mice showed a loss of IL-4 signal transduction and functional activity. The lack of IL-4Rα resulted in markedly diminished, but not absent, TH2 responses after infection with the helminthic parasite Nippostrongylus brasiliensis. CD4⁺, CD62L-high, and CD62L-low T cell populations from uninfected IL-4Rα^−/− mice were isolated by cell sorting. Upon primary stimulation by T cell receptor cross-linkage, the CD62L-low, but not the CD62L-high, cells secreted considerable amounts of IL-4, which was strikingly enhanced upon 4-day culture with anti-CD3 in the presence or absence of IL-4. CD62L-low cells isolated from IL-4Rα^−/−, β₂-microglobulin^−/− double homozygous mice produced less IL-4 than did either IL-4Rα^−/− or wild-type mice. These results indicate that an IL-4-independent, β₂-microglobulin-dependent pathway exists through which the CD62L-low CD4⁺ population has acquired IL-4-producing capacity in vivo, strongly suggesting that these cells are NK T cells.