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Review
. 2009 Feb;9(2):125-35.
doi: 10.1038/nri2476.

GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation

I-Cheng Ho  1 , Tzong-Shyuan Tai, Sung-Yun Pai
Affiliations
Review

GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation

I-Cheng Ho et al. Nat Rev Immunol. 2009 Feb.

Abstract

Many advances in our understanding of the molecules that regulate the development, differentiation and function of T cells have been made over the past few years. One important regulator of T-cell differentiation is the transcription factor GATA-binding protein 3 (GATA3). Although the main function of GATA3 is to act as a master transcription factor for the differentiation of T helper 2 (T(H)2) cells, new research has helped to uncover crucial functions of GATA3 in T cells that go beyond T(H)2-cell differentiation and that are important at earlier stages of haematopoietic and lymphoid-cell development. This Review focuses on the functions of GATA3 from early thymocyte development to effector T-cell differentiation. In addition, we discuss the interactions between GATA3 and other transcription factors and signalling pathways, and highlight the functional significance of the GATA3 protein structure.

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Figures

Figure 1
Figure 1. Functional domains and essential amino acids in mouse GATA3
GATA-binding protein 3 (GATA3) has two amino-terminal transactivation domains TA1 and TA2, and two zinc-finger motifs, which are each followed by a conserved basic region. The C-terminal (proximal) zinc-finger motif binds the canonical GATA motif, WGATAR (where W denotes A or T, and R denotes A or G). The N-terminal (distal) zinc-finger motif seems to have broader specificity, such that the fourth position of the GATA motif can be any nucleotide. Amino acid residues marked in blue were shown in a recent crystal structure of the distal zinc-finger motif to make direct contact with DNA. Arginine 364 inserts deeply into the minor groove of DNA and mutation of this residue to alanine significantly disrupts binding to the WGATAR motif. Residues marked in red have been shown to be involved in GATA3 function. For example, mutation of the amino acids KRR between the two zinc-finger motifs confers dominant negative or hypomorphic function. The YxKxHxxxRP motif (where x indicates any amino acid) is conserved between species, and mutation of any amino acid in this motif abrogates T helper 2 (TH2)-type cytokine production and DNA binding. Methionine 368 in GATA3 (which is equivalent to proline 321 in GATA4) seems to be involved in the efficient induction of interleukin-13 (IL-13) production by GATA3. The NRPL motif that follows the distal zinc-finger motif forms the interface between two GATA3 molecules recognizing DNA sequences that contain closely arranged GATA motifs, which indicates that it may have a role in GATA3 homodimerization.
Figure 2
Figure 2. Transcriptional regulation of positive selection, CD4/CD8-lineage commitment and post-commitment development of thymocytes
Positive selection and CD4- versus CD8-lineage commitment of developing thymocytes are depicted occurring sequentially. The transition from the CD4midCD8mid stage to the CD4hiCD8mid stage is controlled by the transcription factor TOX (thymus high-mobility group box protein). In the absence of TOX expression, CD4midCD8mid cells develop by ‘default’ into CD8 single positive (SP) thymocytes. The commitment of CD4hiCD8mid cells to either the CD4 SP or CD8 SP lineage requires the expression of ThPOK (T-helper-inducing POZ/Kruppel-like factor) or RUNX (runt-related transcription factor) transcription factors, respectively. Recent data show that ThPOK expression by CD4hiCD8mid cells is controlled by GATA3. The further maturation of committed CD4+ SP thymocytes is dependent on MYB and GATA3.
Figure 3
Figure 3. GATA3 is required for both STAT6-dependent and STAT6-independent pathways of TH2-cell differentiation
a | T helper 2 (TH2)-cell differentiation can be initiated by interleukin-4 (IL-4) derived from activated TH cells through signal transducer and activator of transcription 6 (STAT6)-dependent signalling and upregulation of GATA-binding protein 3 (GATA3) expression. TH2-cell differentiation can also be initiated independently of IL-4 receptor (IL-4R) signalling. Various Notch ligands expressed by antigen-presenting cells can interact with Notch of naive CD4+ T cells, leading to the cleavage of transmembrane Notch to release the active intracellular domain of Notch (ICD). ICD then interacts with recombination-signal-binding protein for Igκ J region (RBP-J) and converts it into a transcriptional activator, which allows it to recruit Mastermind-like 1 (MAML1) and p300. The ICD–RBP-J–MAML1–p300 complex can bind to and transactivate the distal promoter of Gata3, which is located upstream of exon 1a, and subsequently leads to the production of IL-4 by the newly activated CD4+ T cells. IL-2 can activate STAT5, which binds to two DNase I hypersensitive sites in the second intron of IL4, resulting in the production of IL-4. Signals through the T-cell receptor (TCR) can also induce early IL-4 production, a process that is probably mediated by nuclear factor-κB (NF-κB). The binding sites for STAT6 or NF-κB in Gata3 remain to be determined. b | The initial burst of GATA3 and IL-4 expression induced dependently or independently of STAT6 then reinforces the expression of GATA3 through the a positive-feedback loop or GATA3 auto-activation. The cis-acting element that is responsible for GATA3 auto-activation is unknown. GATA3 modifies the IL4, IL13 and IL5 loci to create a conformation that is accessible to various other transcription factors that are involved in driving the differentiation of T cells into TH2 cells.
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