IL-4 plays a central role in naive CD4+ T cell differentiation into Th2 cells, but its initial sources and the cellular and molecular basis for the initiation of IL-4 expression have remained elusive. Gene targeting of the c-Maf protooncogene, the cellular homologue of the avian viral oncogene c-Maf, has elucidated the critical role of this basic region/leucine zipper transcription factor for its selective function in IL-4 gene transcription but how the c-Maf gene is regulated is not clear. IL-6 has been shown to induce IL-4 production and promote Th2 differentiation. Our current studies demonstrate that IL-6 rapidly upregulates c-Maf transcription, and this induction requires both IL-6 initiated signaling and TCR activation. Unlike IL-6, IL-4 does not regulate early c-Maf expression. Our proposal presents a new mechanism for how early IL-4 expression is regulated, end how the immune system commits to Th2 development. We hypothesize that IL-6 derived from antigen presenting cells activates Stat3 in naive CD4+ T cells. Stat3 activation combined with antigen stimulation initiates c-Maf and subsequently regulates early IL-4 gene expression. The amount of IL-4 produced at early stages of immune responses plays a critical role in Th2 commitment to initiate the IL-4/Stat6/GATA-3 Th2 developmental cascade. GATA-3 upregulation further enhances c-Maf expression and IL-4 production, and maintains stable Th2 chromatin structure and type 2 effector cell functions. To address this hypothesis we propose these specific aims: 1) To determine the intracellular signaling mechanisms required for IL-6 initiated c-Maf expression; 2) To determine how signals from TCR and IL-6 regulate c-Maf promoter activities; and 3) To determine how IL-6 mediated c-Maf induction may regulate IL-4 production and Th2 differentiation.
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