GATA3 controls the expression of CD5 and the T cell receptor during CD4 T cell lineage development

Abstract

The transcription factor GATA3 is essential at multiple stages of T cell development, including the earliest double-negative stages, b-selection and CD4 single-positive thymocytes. Here, we show that in CD2-GATA3 transgenic mice, with enforced GATA3 expression driven by the CD2 promoter, thymocytes have reduced levels of CD5, which is a negative regulator of TCR signaling participating in TCR repertoire fine-tuning. Reduction of CD5 expression was most prominent in CD4 + CD8 + double-positive (DP) cells and was associated with increased levels of the transcription factor E2A. Conversely, GATA3-deficient DP thymocytes showed consistently higher CD5 levels and defective TCR up-regulation during their development towards the CD4 lo CD8 lo subpopulation. CD2-GATA3 transgenic mice carrying the MHC class II-restricted TCR DO11.10 also manifested decreased CD5 levels. As in these TCR-transgenic mice reduced CD5 expression cannot result from an effect of GATA3 on repertoire selection, we conclude that enforced GATA3 interferes with the developmentally regulated increase of CD5 levels. Enforced GATA3 expression in DO11.10 transgenic mice was also accompanied by enhanced TCR expression during CD4 positive selection. Because GATA3 is induced by TCR signaling in DP thymocytes, our findings indicate that GATA3 establishes a positive feedback loop that increases TCR surface expression in developing CD4 lineage cells.

Cyclooxygenase-2 in mucosal DC mediates induction of regulatory T cells in the intestine through suppression of IL-4

“…CD2-GATA-3 Tg and DO11.10 × CD2-GATA-3 mice were generated as described earlier. 51 All mice were kept under routine animal housing conditions and experiments were approved by the animal experimental committee of the VUMC or the Erasmus MC.…”

Distinct functions for the transcription factors GATA-3 and ThPOK during intrathymic differentiation of CD4+ T cells

“…However, unlike the Zbtb7b hd mutation, Gata3 disruption arrested the development of MHCII-restricted thymocytes during the DP to CD4 SP transition but did not result in redirection to the CD8 lineage12. Conversely, enhanced Gata3 expression failed to redirect MHCI-restricted thymocytes into the CD4 lineage11,14. These observations led to the conclusion that Gata3 controls a post-commitment differentiation or survival step during CD4 T cell development9,12.…”

“…During positive selection, Gata3 expression peaks during the DP to CD4 SP transition, and decreases during the DP to CD8 SP transition10,11. Targeted disruption of Gata3 in DP thymocytes demonstrated that this factor is necessary for the development of CD4 but not CD8 T cells12-14. However, unlike the Zbtb7b hd mutation, Gata3 disruption arrested the development of MHCII-restricted thymocytes during the DP to CD4 SP transition but did not result in redirection to the CD8 lineage12.…”

Enforced expression of GATA3 allows differentiation of IL‐17‐producing cells, but constrains Th17‐mediated pathology

“…In activated Th2 cells GATA3, STAT6, c-Maf and the chromatinremodeling enzyme Brg1 and RNA polymerase II are all bound across the Th2 locus, whereby densely looped, transcriptionally active chromatin is packaged by the special AT-rich sequence binding protein (SATB1) [13]. Furthermore, GATA3 activity is required during embryonic development [14] and at multiple stages of thymocyte development, including the earliest double negative stages [15,16], b-selection [17] and CD4 1 cell development [17][18][19].…”