An interleukin 4 (IL-4)-independent pathway for CD4(+) T cell IL-4 production is revealed in IL-4 receptor-deficient mice

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(−/−), β(2)-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, β(2)-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.