Conventional, naive CD4+ T cells provide an initial source of IL-4 during Th2 differentiation

IL-4 is known to promote the differentiation of CD4(+) T cells into IL-4-secreting Th2 cells. However, the cellular source of the early burst of IL-4 that drives Th2 responses in vivo has not been conclusively identified. Mice deficient for the IL-4 receptor alpha-chain (IL-4R alpha(-/-)) retain the capacity to secrete IL-4 and can be used to identify those cell types that produce IL-4 without a requirement for prior IL-4-mediated stimulation. To address whether naive, conventional CD4(+) T cells may act as initial producers of IL-4 in Ag-specific responses, we crossed the BALB/c IL-4R alpha(-/-)mice to DO11.10/scid TCR transgenic mice. Lymph node cells from wild-type and IL-4R alpha(-/-) DO11.10/scid mice secreted similar to 50 pg of IL-4 per 10(6) cells within 48 h after peptide stimulation. This small amount of IL-4 was sufficient to cause the differentiation of wild-type CD4(+) T cells into Th2 cells, particularly if IFN-gamma and IL-12 were neutralized during the priming cultures. CD4(+) cells from the IL-4R alpha(-/-) mice gave rise to a minor proportion (similar to 2%) of IL-4-producing cells upon stimulation in the presence of anti-IFN-gamma and anti-IL-12, These data show that conventional, naive CD4(+) T cells may be considered as initial sources of IL-4 and, in the absence of IFN-gamma and IL-12, this IL-4 can induce Th2 polarization.