? The differentiation from naive CD4+ T cells into Thl and Th2 effector subsets having distinct cytokine expression profiles is crucial to mounting an appropriate and effective response to antigenic challenge. While the paradigm of Thl and Th2 cell development is widely acknowledged, the molecular mechanisms driving this process are incompletely understood. In addition to the signature cytokines that each subset produce, the expression of Fas ligand (CD95L, FasL) has been demonstrated to be limited to Thl cells and therefore is an appropriate subject to begin to study the basis of CD4+ T cell phenotype development. It has been demonstrated that members of the NF-AT and early growth response (Egr) families are important for maximal activation-induced expression of FasL, though in what capacity each member contributes to optimal expression is unknown. It has also been shown that FasL-expressing Thl cells lack expression of Egr-3 whereas Egr-3 expression is easily detected in FasL-deficient Th2 cells. The hypothesis to be tested is that a cooperative interaction of Egr and NF-AT family members acting directly at the FasL promoter is required for optimal expression and that Egr-3 can function as a competitive regulator, suppressing FasL expression. A broader hypothesis, founded on the differential expression of Egr-3 in Thl and Th2 cells in the FasL transcriptional regulation model, posits that Egr factors play a pivotal role in the generation of effector T cell subsets.
The specific aims will focus on demonstrating that a cooperative interaction of Egr and NF-AT family members acting directly at the FasL promoter is required for optimal FasL expression, that Egr-3 has negative regulatory properties of Egr-3 with respect to FasL expression, and that Egr factors are involved in Thl and Th2 subset development. ? ?
| Lee, Yun Kyung; Mukasa, Ryuta; Hatton, Robin D et al. (2009) Developmental plasticity of Th17 and Treg cells. Curr Opin Immunol 21:274-80 |
| Schraml, Barbara U; Hildner, Kai; Ise, Wataru et al. (2009) The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature 460:405-9 |
| Hatton, Robin D; Harrington, Laurie E; Luther, Rita J et al. (2006) A distal conserved sequence element controls Ifng gene expression by T cells and NK cells. Immunity 25:717-29 |
