HD mice: A novel mouse mutant with a specific defect in the generation of CD4+ T cells

Fox Chase Cancer Center, Filadelfia, Pennsylvania, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/1998; 95(14). DOI: 10.1073/pnas.95.14.8187
Source: PubMed Central


We have identified a spontaneous mutation in mice, which we term HD for “helper T cell deficient.” This mouse is distinguished by the virtual absence of peripheral T cells of the CD4+8− major histocompatibility complex (MHC) class II-restricted T helper subset due to a specific block in thymic development. The developmental defect is selective for CD4+8− cells; the maturation of CD4−8+ and γδ T cells is normal. The autosomal recessive mutation underlying the HD phenotype is unrelated to MHC class II, since it segregates independently of the MHC class II locus. Moreover, the HD phenotype is not caused by a defect of the CD4 gene. Bone marrow transfer experiments demonstrate that the defect is intrinsic to cells of the hematopoietic lineage, i.e., most likely to developing thymocytes themselves. The frequency of CD4+8low intermediate cells is markedly increased in HD mice, suggesting that class II-restricted thymocytes are arrested at this stage. This is the first genetic defect of its kind to be described in the mouse and may prove highly informative in understanding the molecular pathways underlying lineage commitment.

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Available from: Richard Hardy, Oct 02, 2015
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    • "ThPOK (also known as cKrox; encoded by the Zbtb7b gene, referred to here as Thpok) is a member of the BTB/POZ domain-containing zinc-finger transcription factor family [56, 57]. ThPOK was identified by Kappes and colleagues [58] by uncovering the molecular cause of the phenotype of HD (helper-deficient) mice, which lack mature CD4+ T cells, and independently by Bosselut and colleagues [59] as a factor induced in DP thymocytes upon MHC class II-mediated positive selection that promotes CD4 lineage development. HD mice acquired a spontaneous point mutation in Thpok, leading to an amino acid exchange in the third Zn-finger domain of ThPOK [60]. "
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    ABSTRACT: The differentiation and function of peripheral helper and cytotoxic T cell lineages is coupled with the expression of CD4 and CD8 coreceptor molecules, respectively. This indicates that the control of coreceptor gene expression is closely linked with the regulation of CD4/CD8 lineage decision of DP thymocytes. Research performed during the last two decades revealed comprehensive mechanistic insight into the developmental stage- and subset/lineage-specific regulation of Cd4, Cd8a and Cd8b1 (Cd8) gene expression. These studies provided important insight into transcriptional control mechanisms during T cell development and into the regulation of cis-regulatory networks in general. Moreover, the identification of transcription factors involved in the regulation of CD4 and CD8 significantly advanced the knowledge of the transcription factor network regulating CD4/CD8 cell-fate choice of DP thymocytes. In this review, we provide an overview of the identification and characterization of CD4/CD8 cis-regulatory elements and present recent progress in our understanding of how these cis-regulatory elements control CD4/CD8 expression during T cell development and in peripheral T cells. In addition, we describe the transcription factors implicated in the regulation of coreceptor gene expression and discuss how these factors are integrated into the transcription factor network that regulates CD4/CD8 cell-fate choice of DP thymocytes.
    Cellular and Molecular Life Sciences CMLS 06/2013; 70(23). DOI:10.1007/s00018-013-1393-2 · 5.81 Impact Factor
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    • "We found that Zbtb7b is the member of the BTB-ZF family that shows the highest level of expression in the olfactory epithelium. Zbtb7b, also known as Th-POK (for T-helper-inducing POZ/Krüppel factor), was shown to be essential for CD4 cell fate decision during T lymphocyte development [52], [53] and it was first identified as the gene that is mutated in a spontaneous mouse mutant, termed ‘helper deficient’ (HD), which lacked CD4 cells [54], [55]. It has been shown that Zbtb7b (ThPOK) is expressed in CD4 cells (but not in CD8 cells) where it prevents the expression of CD8 lineage genes, thereby promoting CD4 lineage commitment [53]. "
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    ABSTRACT: In mammals, odorants and pheromones are detected by hundreds of odorant receptors (ORs) and vomeronasal receptors (V1Rs and V2Rs) expressed by sensory neurons that are respectively located in the main olfactory epithelium and in the vomeronasal organ. Even though these two olfactory systems are functionally and anatomically separate, their sensory neurons show a common mechanism of receptor gene regulation: each neuron expresses a single receptor gene from a single allele. The mechanisms underlying OR and VR gene expression remain unclear. Here we investigated if OR and V1R genes share common sequences in their promoter regions. We conducted a comparative analysis of promoter regions of 39 mouse V1R genes and found motifs that are common to a large number of promoters. We then searched mouse OR promoter regions for motifs that resemble the ones found in the V1R promoters. We identified motifs that are present in both the V1R and OR promoter regions. Some of these motifs correspond to the known O/E like binding sites while others resemble binding sites for transcriptional repressors. We show that one of these motifs specifically interacts with proteins extracted from both nuclei from olfactory and vomeronasal neurons. Our study is the first to identify motifs that resemble binding sites for repressors in the promoters of OR and V1R genes. Analysis of these motifs and of the proteins that bind to these motifs should reveal important aspects of the mechanisms of OR/V1R gene regulation.
    PLoS ONE 12/2011; 6(12):e29065. DOI:10.1371/journal.pone.0029065 · 3.23 Impact Factor
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    • "Several transcription factors essential for CD4/CD8 T cell lineage commitment have been identified, including the Runx factors, as well as TOX, GATA3 and Th-POK [36], [37], [38], [39], [40], [41], [42], [43]. Among these transcription factors, Th-POK has been identified as a master enforcer of CD4 commitment [44], [45], [46], [47]. Th-POK is a Zn finger transcription factor, and is expressed specifically in the CD4 lineage. "
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    ABSTRACT: T cell development is critically dependent on both the environment and signals delivered by the T cell Receptor (TCR). The Tec family kinase Itk has been suggested to be an amplifier of signals emanating from the TCR and the loss of Itk partially affects most stages of thymopoiesis. Loss of Itk also differentially affects the development of conventional vs. non-conventional or innate memory phenotype T cells. Here, we examine whether these lineage choices are affected by a combination of TCR affinity and Itk by analyzing mice lacking Itk and carrying two TCR transgenes with differing affinities, OT-II and DO11.10. Our results show that developing thymocytes receive a gradient of signals, DO11.10>OT-II>DO11.10/Itk(-/-)>OT-II/Itk(-/-). We also show that the development of CD4(+) T cells is controlled by TCR signaling via Itk, which regulates the expression of the transcription factor, Th-POK, an enforcement factor for CD4 commitment. This results in a reduction in CD4(+) T cell development, and an increase in the development of MHC class II restricted TCR transgenic CD8(+) T cells that resemble non-conventional or innate memory phenotype CD8 T cells. This alteration accompanies increased expression of Runx3 and its target genes Eomesodermin, Granzyme B and Perforin in Itk null OT-II CD4(+) thymocytes. All together, these data suggest that Itk plays an important role in CD4/CD8 commitment by regulating signal thresholds for the lineage commitment. Our data also suggest that the lower level of TCR signaling that occurs with a low affinity TCR in the absence of Itk can redirect some MHC class II restricted CD4(+) T cell to class II-restricted CD8(+) innate memory phenotype T cells.
    PLoS ONE 01/2010; 5(1):e8891. DOI:10.1371/journal.pone.0008891 · 3.23 Impact Factor
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