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.
| Xu, Jiangnan; Yang, Yu; Qiu, Guixing et al. (2011) Stat4 is critical for the balance between Th17 cells and regulatory T cells in colitis. J Immunol 186:6597-606 |
| Xu, Jiangnan; Yang, Yu; Qiu, Guixing et al. (2009) c-Maf regulates IL-10 expression during Th17 polarization. J Immunol 182:6226-36 |
| Yang, Yu; Xu, Jiangnan; Niu, Yanyan et al. (2008) T-bet and eomesodermin play critical roles in directing T cell differentiation to Th1 versus Th17. J Immunol 181:8700-10 |
| Yang, Yu; Ochando, Jordi C; Bromberg, Jonathan S et al. (2007) Identification of a distant T-bet enhancer responsive to IL-12/Stat4 and IFNgamma/Stat1 signals. Blood 110:2494-500 |
