Direct Regulation of Gata3 Expression Determines the T Helper Differentiation Potential of Notch

Abstract

CD4(+) T helper cells differentiate into T helper 1 (Th1) or Th2 effector lineages, which orchestrate immunity to different types of microbes. Both Th1 and Th2 differentiation can be induced by Notch, but what dictates which of these programs is activated in response to Notch is not known. By using T cell-specific gene ablation of the Notch effector RBP-J or the Notch1 and 2 receptors, we showed here that Notch was required on CD4(+) T cells for physiological Th2 responses to parasite antigens. GATA-3 was necessary for Notch-induced Th2 differentiation, and we identified an upstream Gata3 promoter as a direct target for Notch signaling. Moreover, absence of GATA-3 turned Notch from a Th2 inducer into a powerful inducer of Th1 differentiation. Therefore, Gata3 is a critical element determining inductive Th2 differentiation and limiting Th1 differentiation by Notch.

The Notch signaling pathway: Transcriptional regulation at Notch target genes

“…CD25 (IL2-R and preTa, pre-T-cell receptor alphachain) were also shown to be Notch target genes in T-cells [19,20]. In later stages of T-cell development, the transcription factor GATA3, a master regulator for Tcell development and later for Th1/2 lineage decision, is a direct Notch target gene [21,22]. Flavell and colleagues could show that Th2-mediated immunity depends on either RBP-J or Notch [22] and that the GATA3 promoter contains bona fide RBP-J binding sites.…”

“…In later stages of T-cell development, the transcription factor GATA3, a master regulator for Tcell development and later for Th1/2 lineage decision, is a direct Notch target gene [21,22]. Flavell and colleagues could show that Th2-mediated immunity depends on either RBP-J or Notch [22] and that the GATA3 promoter contains bona fide RBP-J binding sites. In addition, the Pear lab demonstrated, that the expression of dominant-negative mastermindlike-1 (dnMAML) results in impaired GATA3 transcription levels and subsequently impaired IL4 production [21].…”

“…Recent data also indicate that Notch signaling can direct the differentiation and activity of peripheral T-cells, reviewed in [107,141]. During helper T-cell differentiation, Notch is involved in generating optimal Th2 cell responses by upregulating GATA3 and thereby promoting IL-4 expression [21,22].…”

Th17 cells: new players in asthma pathogenesis

“…However, the cell and the mechanisms responsible for this early IL-4 production remained unclear for a long time. Only recently, it was found that IL-4 could be produced by the naı¨ve Th cell itself, upon Notch triggering, as a consequence of the expression by the dendritic cell (DC) of its ligand Jagged-1 in both mice and humans (50,51). Another possibility is the production by other cell types, such as mast cells and macrophages present in the gut of worm-infested animals or lung epithelial cells, of a more recently discovered cytokine, named as IL-25.…”

Correlation of Notch1/Hes1 Genes Expression Levels in Egyptian Paediatric Patients with Newly Diagnosed and Persistent Primary Immune(Idiopathic) Thrombocytopenic Purpura

“…It regulates multiple steps of T and B cell development, T cell activation, regulatory T-cell function and T-helper cell differentiation [7][8][9][10][11]. Furthermore, it helps in the development and differentiation of many other hematopoietic and immune cells [12].…”