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

Key Points

  • GATA-binding protein 3 (GATA3) is a zinc-finger transcription factor that is continually expressed in a highly regulated manner throughout T-cell development and CD4+ T helper (TH)-cell differentiation.

  • At the earliest stages of T-cell development, GATA3 is required for commitment to the T-cell lineage. However, forced expression of GATA3 in pre-committed double negative 1 (DN1) or DN2 thymocytes is toxic, and in developing B cells it diverts the development of cells to the mast-cell lineage. So, the expression levels of GATA3 must be 'just right' for successful commitment to the T-cell lineage.

  • After T-cell-lineage commitment, GATA3 has a role in β-selection, such that mice lacking GATA3 at the DN3 stage of development exhibit partial arrest at the DN3 stage and impairment of T-cell receptor β-chain (TCRβ) protein expression. The nature and extent of this function of GATA3 are still unclear owing to the current limitations of T-cell-specific conditional knockout technology.

  • Two transcription factors, GATA3 and T-helper-inducing POZ/Kruppel-like factor (ThPOK; encoded by Zbtb7b, which was recently found to be mutated in the helper-deficient spontaneous mutant mouse strain), are both crucial for CD4 single positive (SP) thymocyte development. The development of MHC class II-restricted thymocytes that lack or express a mutant form of ThPOK is diverted to the CD8 lineage, indicating that ThPOK functions in CD4- or CD8- lineage determination. By contrast, GATA3-deficient thymocytes that develop in a MHC class II-restricted environment give rise to no or few CD8-lineage cells. Delineating the distinct functions of these two factors is further complicated by evidence showing that GATA3 upregulates ThPOK expression but restoration of ThPOK expression in GATA3-deficient mice fails to restore CD4 SP thymocyte development.

  • GATA3 is both necessary and sufficient for the development of TH2 cells, largely because interleukin-4 receptor (IL-4R) signalling through signal transducer and activator of transcription 6 (STAT6) induces GATA3 expression in a positive-feedback loop. STAT6-independent TH2-cell differentiation signals, such as triggering of the TCR, activation of IL-2R–STAT5A signalling and engagement of Notch receptors, also depend on GATA3 to promote IL-4 production.

  • Control of the production of individual TH2-type cytokines by GATA3 is accomplished by distinct mechanisms, as shown by structure–function analyses.

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 (TH2) cells, new research has helped to uncover crucial functions of GATA3 in T cells that go beyond TH2-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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Figure 1: Functional domains and essential amino acids in mouse GATA-binding protein 3.
Figure 2: Transcriptional regulation of positive selection, CD4- or CD8-lineage commitment and post-commitment development of thymocytes.
Figure 3: GATA-binding protein 3 is required for both STAT6-dependent and STAT6-independent pathways of T-helper-2-cell differentiation.

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Acknowledgements

Owing to space constraints, we could not include every relevant reference and apologize to our colleagues whose work we did not mention. This work is supported by a R01 grant AI054451 (to I.-C.H.) and a K08 award (AI050601 (to S.-Y.P.) from the National Institutes of Health, USA, a Charles H. Hood Foundation Child Health Research Grant (to S.-Y.P.), and a Merit Scholarship (to T.-S.T.) from National Science Council, Taiwan.

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Glossary

Zinc-finger motif

A DNA-binding domain in which cysteine and histidine residues are coordinated by zinc atoms and thereby form 'fingers' that bind to DNA.

Natural killer T (NKT) cells

A subpopulation of T cells that expresses both NK- and T-cell markers. In the C57BL/6 mouse strain, NKT cells express the NK1.1 (NKRP1C) molecule and the T-cell receptor (TCR). Some NKT cells recognize CD1d-associated lipid antigens and express a restricted repertoire of TCRs. After TCR stimulation of naive mice, NKT cells rapidly produce interleukin-4 and interferon-γ.

β-selection

The controlled developmental transition beyond the double negative 3 (DN3) stage to the double-positive stage that is limited to T cells which have successfully rearranged their T-cell receptor (TCR) β-chain genes to express a functional cell-surface pre-TCR. The conditional developmental arrest encountered at the DN3 stage is termed the β-selection checkpoint.

Fetal thymic organ culture

(FTOC). A system for culturing fetal thymi on a filter that is suspended over culture medium. FTOC allows the growth of the organ for a longer period than would be allowed by the viability of the embryo and/or under various experimental conditions (for example, by the addition of growth factors to the medium).

Double negative (DN) subset

The most immature thymocytes, which lack expression of the co-receptors CD4 and CD8. This compartment can be further subdivided on the basis of CD44 and CD25 expression into four subpopulations: DN1 (CD25-CD44+), DN2 (CD25+CD44+), DN3 (CD25+CD44) and DN4 (CD25CD44).

OP9–DLL1 culture system

A culture system in which stromal cells that are derived from osteopetrotic Op/Op mice (OP9 cells) are stably transduced to overexpress the Notch ligand Delta-like ligand 1 (DLL1) to promote T-cell lineage development of co-cultured progenitor cells. OP9 cells are useful in co-cultures that are initiated with myeloid progenitor cells because they do not produce macrophage colony-stimulating factor 1, which can cause excessive generation of macrophages and prevent the development of lymphoid cells.

Positive selection

The process by which immature CD4+CD8+ thymocytes expressing T-cell receptors with low affinity and/or avidity for self-peptide– MHC complexes are induced to differentiate into mature CD4+ and CD8+ thymocytes.

Negative selection

The process by which CD4+CD8+ thymocytes expressing potentially autoreactive T-cell receptors are induced to undergo apoptosis in the thymus.

Cre–loxp technology

A site-specific recombination system that is used to delete a gene in mouse cells using Cre recombinase. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Expression of Cre recombinase leads to excision of the intervening sequence. Depending on the type of promoter, Cre can be expressed at specific times during development or by specific sets of cells, including embryonic stem cells.

Annexin V

A molecule that binds phosphatidylserine, which is usually located on the inner leaflet of the plasma membrane but flips to the outer leaflet during apoptosis. Positive staining with annexin V is an indicator of apoptosis.

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Ho, IC., Tai, TS. & Pai, SY. GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation. Nat Rev Immunol 9, 125–135 (2009). https://doi.org/10.1038/nri2476

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