T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia

Abstract

IntroductionAplastic anemia, the paradigm of bone marrow failure syndromes, is characterized by peripheral blood pancytopenia and an empty bone marrow. 1 In most cases, aplastic anemia is an immunemediated disease with active destruction of hematopoietic cells by T lymphocytes. 2 The aberrant immune response may be triggered by drugs, virus, or chemical exposure, but in the majority of cases there is no obvious etiologic factor. 3,4 The clinical observations that most patients respond to immunosuppressive treatment with cyclosporine and antithymocyte globulin-based regimens 5,6 is the most powerful evidence for the pivotal role of the immune system in the pathophysiology of aplastic anemia. Excessive production of interferon-␥ (IFN-␥), tumor necrosis factor (TNF), and interleukin-2 (IL-2) from patients' T cells suggests that the hematopoietic cells are destroyed through a Th1 T-cell response. [7][8][9][10][11] This Th1 "shift" in aplastic anemia results in both Fas-mediated cell death and inhibition of hematopoietic stem cell proliferation. 2,12 Oligoclonal expansion of cytotoxic T lymphocytes (CTLs) correlates with disease activity. 13,14 In an animal model of aplastic anemia, injection of alloreactive lymphocytes results in bone marrow failure, but pancytopenia can be prevented with anti-IFN-␥ and anti-TNF monoclonal antibody. 15 IFN-␥, the hallmark cytokine of the Th1 immune response, is produced primarily by T cells and natural killer (NK) cells. Following activation, naive T cells differentiate into Th1 CD4 ϩ and cytotoxic CD8 ϩ cells that secrete IFN-␥ and other cytokines, and Th2 CD4 ϩ cells that produce IL-4 and other cytokines. Two transcription factors are responsible for the shift of CD4 ϩ T cells into the Th1 or Th2 phenotype: T-bet for Th1 and GATA-3 for Th2. 16,17 IFN-␥ is also produced when T cells are stimulated with IL-12 or IL-18 secreted by antigen-presenting cells (APCs). Regulation of IFN-␥ production occurs primarily at the level of transcription. 18 The proximal site of the IFN-␥ gene (Ϫ75 to Ϫ45 bp of the IFN-␥ promoter) is a binding site for nuclear factor for activated T cells (NFATs), AP-1, ATF, and CREB transcription factors. 19,20 In the proximal IFN-␥ promoter site, a half T-box sequence allows T-bet binding, resulting in increased IFN-␥ production. 21 T-bet is a member of the T-box family of transcription factors. 22 This family contains a highly conserved DNA binding domain, the T-box. T-box binds to a specific sequence in the promoter of different genes. T-bet is found in Th1 but not in Th2 cells and is the key regulator of Th1 development and function. 16,23 Mice lacking T-bet fail to develop Th1 cells and are driven toward Th2-mediated disease. 24 Overexpression of T-bet in Th2 cells results in loss of the Th2 phenotype and increased production of IFN-␥. 16 Activated T cells result in increased T-bet expression, which induces IL-12R␤2 expression. 25 T-bet also positively regulates its own expression through an autoregulator loop involving Hlx, a homeobox gene. 26 T-cell engagem...

Network model of survival signaling in large granular lymphocyte leukemia

“…It also inhibits the production of IL-2, which is known to be absent in leukemic T-LGL and in T EMRA (23,32). T-bet has been related to multiple autoimmune diseases in humans (33)(34)(35)(36). T-LGL leukemia has important overlaps with autoimmune disorders, particularly rheumatoid arthritis (2).…”

“…Nuclear and cytoplasmic extract from patient and normal PBMCs were prepared by using TransFactor Extraction Kit according to manufacturer's instructions. Probes for NF B (5Ј-GATCCGGCAGGGGAATCTCCCTCTC-3Ј) (20), STAT3 (5Ј-CTTCATTTCCCGTAAATCCCTA) (3) and T-bet (5Ј-AAAACTTGT-GAAAATACGTAATCCTCAG-3Ј) (34)were biotinylated at 5Ј. Corresponding nonbiotinylated oligonucleotides were used as competition oligonucleotides.…”

PKC-θ-Deficient Mice Are Protected from Th1-Dependent Antigen-Induced Arthritis

“…Recent work established that T-bet protein levels correlate with disease activity in patients with aplastic anemia and that T-bet expression levels may be an indicator of disease activity (12). We compared T-bet expression in the spleens of wild-type mice and PKC--deficient mice during disease development.…”

Identification of novel microRNA signatures linked to acquired aplastic anemia

“…4 Constitutive expression of T-bet, a transcriptional regulator that is critical to Th1 polarization, is present in the majority of AA patients. 5 Genome-wide transcriptional analysis of T cells from AA patients has implicated some components of innate immunity in AA, including Toll-like receptors and natural killer cells. 6 However, the precise mechanisms underlying activation of T cells in AA are still unclear.…”