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Helper Cell Differentiation (helper + cell_differentiation)
Selected AbstractsNotch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2005Sascha Rutz Abstract The Notch pathway is involved in cell differentiation processes in various organs and at several developmental stages. The importance of Notch for early T lymphocyte development is well established. Recently, Notch has been implicated in directing naive T helper cell differentiation towards the Th1, Th2 or regulatory T cell lineages. However, the molecular events underlying these processes are poorly understood. We show that the Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially affect early T cell activation and proliferation following T cell receptor cross-linking. Delta-like1 and Jagged1 induce a dose-dependent inhibition of early activation markers CD69 and CD25, as well as inhibition of proliferation after anti-CD3 stimulation of purified CD4+ T cells. Similarly, the rapid activation of transcription factors NF-AT, AP-1 and NF-,B is suppressed. In contrast, triggering of Notch by Delta-like4 enhances T cell activation and proliferation. The observed effects are dependent on simultaneous cross-linking of TCR and Notch but independent of ,-secretase-mediated cleavage of Notch. These data suggest direct interference between Notch and early TCR signal transduction events, independent of the classical Notch pathway via release of the Notch intracellular domain. A Notch-mediated alteration of TCR signaling strength may contribute to the recently described modulation of naïve T cell differentiation by Notch ligands. [source] Nuclear repositioning marks the selective exclusion of lineage-inappropriate transcription factor loci during T helper cell differentiationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2004Susannah Abstract To address how heritable patterns of gene expression are acquired during the differentiation of Th1 and Th2 cells, we analyzed the nuclear position of lineage-restricted cytokine genes and their upstream regulators by 3-dimensional fluorescence in situ hybridization. During Th1 differentiation, GATA-3 and c-maf loci, which encode upstream regulators of Th2 cytokines, were progressively repositioned to centromeric heterochromatin as defined by a ,-satellite repeat probe and/or the nuclear periphery, compartments that have been associated with transcriptional repression. A third transcription factor locus, T-bet, which controls Th1-specific programs, was subject to de novo CpG methylation in a Th2 cell clone. In contrast, we did not find repositioning of the cytokine gene loci IL-2, IL-3, IL-4 or IFN-, during T helper cell differentiation. Instead, IFN-, was constitutively associated with the nuclear periphery, even when primed for expression in Th1 cells. Our results suggest that Th1/Th2 lineage commitment and differentiation involve repositioning of the regulators of cytokine expression, rather than the cytokine genes themselves. [source] Common themes emerge in the transcriptional control of T helper and developmental cell fate decisions regulated by the T-box, GATA and ROR familiesIMMUNOLOGY, Issue 3 2009Sara A. Miller Summary Cellular differentiation requires the precise action of lineage-determining transcription factors. In the immune system, CD4+ T helper cells differentiate into at least three distinct effector lineages, T helper type 1 (Th1), Th2 and Th17, with the fate of the cell at least in part determined by the transcription factors T-box expressed in T cells (T-bet), GATA-3 and retinoid-related orphan receptor ,t (ROR,t), respectively. Importantly, these transcription factors are members of larger families that are required for numerous developmental transitions from early embryogenesis into adulthood. Mutations in members of these transcription factor families are associated with a number of human genetic diseases due to a failure in completing lineage-specification events when the factor is dysregulated. Mechanistically, there are both common and distinct functional activities that are utilized by T-box, GATA and ROR family members to globally alter the cellular gene expression profiles at specific cell fate decision checkpoints. Therefore, understanding the molecular events that contribute to the ability of T-bet, GATA-3 and ROR,t to define T helper cell lineages can provide valuable information relevant to the establishment of other developmental systems and, conversely, information from diverse developmental systems may provide unexpected insights into the molecular mechanisms utilized in T helper cell differentiation. [source] |