IL-4-mediated inhibition of IFN-γ production by CD4+ T cells proceeds by several developmentally regulated mechanisms

The mechanisms by which T(h)1 and T(h)2 cells inter-regulate in vivo are still poorly understood. In this study we examined the plasticity of T(h)1 cell differentiation and how T(h)2 cells may down-regulate these responses. We show here that IL-4 affects T(h)1 cell responses by two developmentally regulated mechanisms. During the commitment phase of naive CD4(+) T cells, IL-4 inhibits T(h)1 cell differentiation and induces a reversion of developing T(h)1 cells to the T(h)2 lineage. In contrast, for effector T(h)1 cells IL-4 does not affect the developmental process, but only the transcription of the IFN-gamma gene. We further show that the difference in IL-4 responsiveness correlates with a loss, in effector T(h)1 cells, of IL-4-dependent up-regulation of GATA-3 expression despite normal activation of STAT6. Transient inhibition of IFN-gamma production by differentiated effector cells may explain why T(h)1 and T(h)2 responses can co-exist in vivo although T(h)2 effector cells dominate functionally, as observed in some infectious or autoimmune mice models.