Article

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

Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature Reviews Immunology 02/2009; 9(2):125-35. DOI: 10.1038/nri2476
Source: PubMed

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.

0 Followers
 · 
107 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: TOX is a nuclear factor essential for the development of CD4(+) T cells in the thymus. It is normally expressed in low amounts in mature CD4(+) T cells of the skin and the peripheral blood. We have recently discovered that the transcript levels of TOX were significantly increased in mycosis fungoides (MF), the most common type of cutaneous T cell lymphoma (CTCL) as compared with normal skin or benign inflammatory skin. However, its involvement in advanced CTCL and its biological effects on CTCL pathogenesis have not been explored. In this study, we demonstrate that the TOX expression is also enhanced significantly in primary CD4(+)CD7(-) cells from patients with Sézary syndrome, a leukemic variant of CTCL, and that high TOX transcript levels correlate with increased disease-specific mortality. Stable knockdown of TOX in CTCL cells promoted apoptosis and reduced cell cycle progression, leading to less cell viability and colony-forming ability in vitro, and reduced tumor growth in vivo. Furthermore, TOX knockdown significantly increased two cyclin-dependent kinase inhibitors, CDKN1B and CDKN1C. Finally, blocking CDKN1B and CDKN1C reversed growth inhibition of TOX knockdown. Collectively, these findings provide strong evidence that aberrant TOX activation is a critical oncogenic event for CTCL. Copyright © 2014 American Society of Hematology.
    Blood 12/2014; DOI:10.1182/blood-2014-05-571778 · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Asthma is a serious global health problem characterised by airway inflammation, airway epithelial wall shedding, enhanced mucus production, increased IgE levels and airway hyperresponsiveness. The pathophysiology of asthma is mediated by Th2 cells which produce Th2 cytokines like interleukin-4, interleukin-5, interleukin-13 and interleukin-9. The differentiation of Th2 cells is induced by the transcription factor GATA3 which is activated by pSTAT6 via IL-4 signalling. To investigate the anti-asthmatic potential of Boswellic acid, as well as the underlying mechanism involved, we studied its anti-asthmatic potential in a murine model of asthma. In this study, BALB/c mice were systemically sensitized by ovalbumin (OVA) followed by aerosol allergen challenges. We investigated the effect of Boswellic acid on airway hyperresponsiveness, inflammatory cell infiltration, Th2 cytokine and OVA-specific IgE production in a mouse model of asthma. We found that Boswellic acid treated groups suppressed allergic airway inflammation, AHR, OVA-specific IgE and Th2 cytokines secretion. It also suppressed the expression of pSTAT6 and GATA3 in a dose dependent manner. Our data suggest that the mechanism by which Boswellic acid effectively treats asthma is based on reductions of Th2 cytokines via inhibition of pSTAT6 and GATA-3 expression.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The lifelong generation of αβT cells enables us to continuously build immunity against pathogens and malignancies despite the loss of thymic function with age. Homeostatic proliferation of post-thymic naïve and memory T cells and their transition into effector and long-lived memory cells balance the decreasing output of naïve T cells, and recent research suggests that also αβT-cell development independent from the thymus may occur. However, the sites and mechanisms of extrathymic T-cell development are not yet understood in detail. γδT cells represent a small fraction of the overall T-cell pool, and are endowed with tremendous phenotypic and functional plasticity. γδT cells that express the Vδ1 gene segment are a minor population in human peripheral blood but predominate in epithelial (and inflamed) tissues. Here, we characterize a CD4(+) peripheral Vδ1(+) γδT-cell subpopulation that expresses stem-cell and progenitor markers and is able to develop into functional αβT cells ex vivo in a simple culture system and in vivo. The route taken by this process resembles thymic T-cell development. However, it involves the re-organization of the Vδ1(+) γδTCR into the αβTCR as a consequence of TCR-γ chain downregulation and the expression of surface Vδ1(+)Vβ(+) TCR components, which we believe function as surrogate pre-TCR. This transdifferentiation process is readily detectable in vivo in inflamed tissue. Our study provides a conceptual framework for extrathymic T-cell development and opens up a new vista in immunology that requires adaptive immune responses in infection, autoimmunity, and cancer to be reconsidered.
    Frontiers in Immunology 01/2014; 5:645. DOI:10.3389/fimmu.2014.00645

Full-text (2 Sources)

Download
58 Downloads
Available from
May 27, 2014