Abstract
The differentiation of naive CD4 T cells into Th2 cells requires the T cell receptor-mediated activation of the ERK MAPK cascade. Little is known, however, in regard to how the ERK MAPK cascade regulates Th2 cell differentiation. We herein identified Gfi1 (growth factor independent-1) as a downstream target of the ERK MAPK cascade for Th2 cell differentiation. In the absence of Gfi1, interleukin-5 production and the change of histone modification at the interleukin-5 gene locus were severely impaired. Furthermore, the interferon gamma gene showed a striking activation in the Gfi1(-/-) Th2 cells. An enhanced ubiquitin/proteasome-dependent degradation of GATA3 protein was observed in Gfi1(-/-) Th2 cells, and the overexpression of GATA3 eliminated the defect of Th2 cell function in Gfi1-deficient Th2 cells. These data suggest that the T cell receptor-mediated induction of Gfi1 controls Th2 cell differentiation through the regulation of GATA3 protein stability.
Highlights
Thought to be involved in various inflammatory diseases
We previously reported that Th2 cell differentiation is highly dependent on the extent of TCR-mediated activation of the p56lck, calcineurin, and the Ras-ERK MAPK signaling cascade (14 –16)
TCR-mediated Activation of the ERK MAPK and Calcineurin Pathways Induces Gfi1 mRNA Expression—We previously reported that the TCR-mediated activation of the Ras-ERK MAPK cascade is required for Th2 cell differentiation [15, 17]
Summary
Thought to be involved in various inflammatory diseases. T regulatory cells are known to suppress various immune responses including those of autoimmune diseases [4]. A decrease in IL-5 and an increase in IFN␥ mRNA expression in Gfi1Ϫ/Ϫ Th2 cells were confirmed by quantitative RT-PCR (Fig. 1D).
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