The TH1 cell lineage-determining transcription factor T-bet suppresses TH2 gene expression by redistributing GATA3 away from TH2 genes

Abstract

Lineage-determining transcription factors (LD-TFs) drive the differentiation of progenitor cells into a specific lineage. In CD4+ T cells, T-bet dictates differentiation of the TH1 lineage, whereas GATA3 drives differentiation of the alternative TH2 lineage. However, LD-TFs, including T-bet and GATA3, are frequently co-expressed but how this affects LD-TF function is not known. By expressing T-bet and GATA3 separately or together in mouse T cells, we show that T-bet sequesters GATA3 at its target sites, thereby removing GATA3 from TH2 genes. This redistribution of GATA3 is independent of GATA3 DNA binding activity and is instead mediated by the T-bet DNA binding domain, which interacts with the GATA3 DNA binding domain and changes GATA3′s sequence binding preference. This mechanism allows T-bet to drive the TH1 gene expression program in the presence of GATA3. We propose that redistribution of one LD-TF by another may be a common mechanism that could explain how specific cell fate choices can be made even in the presence of other transcription factors driving alternative differentiation pathways.

L-Theanine Modulates Intestine-Specific Immunity by Regulating the Differentiation of CD4+ T Cells in Ovalbumin-Sensitized Mice

“…TLR signaling is transmitted downstream through myeloid differentiation factor 88 (MyD88) to activate nuclear factor-kappa B (NF-κB)–mediated immune responses . GATA-3 can promote the differentiation of CD4+ T cells to Th1 cells, while T-bet inhibits the differentiation of CD4+ T cells to Th2 cells . As a key transcription factor, RORγt activates Th17 cells to secrete IL-17 .…”

“…12 GATA-3 can promote the differentiation of CD4+ T cells to Th1 cells, while T-bet inhibits the differentiation of CD4+ T cells to Th2 cells. 13 As a key transcription factor, RORγt activates Th17 cells to secrete IL-17. 14 Moreover, Foxp3 can maintain the development and function of Tregs.…”

Rapid qPCR-based quantitative immune cell phenotyping in mouse tissues

“…RT-qPCR primer pairs were designed for well accepted marker genes known to be specific for the cell type of interest and with minimal expression in other cell types. Accordingly, the markers used to detect the target immune cell populations were as follows: CD3 for total T cells 17 CD4 for T helper cells, 18,19 CD8 for cytotoxic T cells, 18,19 T-bet for Th1 cells, 20 CD79 for B cells, 21 and F4/80 for macrophages 22 (Table 1). Next, tissues from different organs such as the spleen, thymus, lymph nodes, and colon with either high, medium or low infiltration of T cells and subpopulations were chosen as target tissues for the development and validation of the method.…”

Transcription factor-driven regulation of ILC1 and ILC3

“…Moreover, preliminary data of fate-mapper and reporter mouse models for T-bet demonstrated that ~5% of intestinal ILC2 express T-bet [ 137 ]. In MLN ILC2, GATA3 appears to bind to an intron in Tbx21 , perhaps resulting from a direct interaction between T-bet and GATA3 as in CD4 + T cells, and perhaps due to the redistribution of GATA3 away from GATA3-target genes [ 79 , 138 ]. This notion is further supported by the greater abundance of intestinal ILC2 in Tbx21 –/– mice relative to wild-type mice, which might indicate that T-bet restrains ILC2 differentiation intrinsically in ILC [ 72 ].…”