A Novel Element Upstream of the Vγ2 Gene in the Murine T Cell Receptor γ Locus Cooperates with the 3′ Enhancer to Act as a Locus Control Region

Baker, Jeanne E.; Kang, Joonsoo; Xiong, Na; Chen, Tempe; Cado, Dragana; Raulet, David H.

doi:10.1084/jem.190.5.669

Cited by 27 publications

(17 citation statements)

References 49 publications

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“…A previous report suggested that a DNase I hypersensitive site between V␥5 and V␥2 genes serves as a locus control region in concert with E␥ (32). Comparison between human and mouse V␥ regions demonstrated that human V␥1.8 and mouse V␥5 and human V␥4P and mouse V␥2 have sequence homology (data not shown).…”

Section: Conserved Stat Motifs In the Human And Mouse Tcr␥ Locimentioning

confidence: 82%

Induction of Germline Transcription in the Human TCRγ Locus by STAT5

Lee

Honjo

et al. 2001

The Journal of Immunology

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TCR and Ig genes are assembled by V(D)J recombination during lymphocyte development. The enhancer and the germline promoter control the accessibility of each locus for the common recombinase activity. In the mouse TCRγ locus, STAT5 proteins activated by the IL-7R interact with consensus motifs in 5′ regions of Jγ segments and induce germline transcription. To evaluate the role of STAT5 in controlling the accessibility of the TCRγ locus, we characterized the germline transcription of human TCRγ genes and compared it with mouse. We first demonstrated that Jγ-Cγ germline transcripts are induced in a cytokine-dependent human erythroleukemia cell line. STAT consensus motifs are present in 5′ regions of Jγ1.1 and Jγ2.1 gene segments, and activated STAT5 binds to these motifs. By using a reporter assay, we showed that the Jγ1.1 germline promoter is transactivated by STAT5 and that mutations in any of the two STAT motifs abrogate this activity. Thus, this study demonstrates that STAT5 induces germline transcription in the TCRγ locus of both mouse and human and suggests the possibility that this mechanism may play an essential role in controlling the TCRγ locus accessibility. In addition, STAT motifs are conserved among 5′ Jγ germline promoters, 3′ enhancers, and a locus control region-like element, HsA, in both mouse and human TCRγ loci, indicating the possibility that IL-7R/STAT5 signaling probably controls the locus-wide accessibility through these elements.

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Section: Conserved Stat Motifs In the Human And Mouse Tcr␥ Locimentioning

confidence: 82%

Induction of Germline Transcription in the Human TCRγ Locus by STAT5

Lee

Honjo

et al. 2001

The Journal of Immunology

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“…It has been shown previously by semi-quantitative chromatin immunoprecipitation (ChIP) assays that the TcrC γ 1 locus in Il7r -/-thymocytes is relatively inaccessible 16,33 . This conclusion was based on the fact that the J γ gene segment, the 3′ enhancer (E Cγ1 ), as well as the locus control region-like element (DNaseI hypersensistive site A, HsA 14,34 ), of the TcrC γ 1 locus are hypoacetylated. The latter two cis-acting elements are redundantly required for transcription of rearranged V γ 2, V γ 4, and V γ 3 genes, but substantially less so for the V γ 5 gene 14 .…”

Section: Il-15 Modulates Chromatin Accessibility Of V γ 5 Genementioning

confidence: 99%

“…PCR and RT-PCR assays to detect Tcrg gene rearrangements and transcripts were performed as described 14,34,35 using primers published and listed in Supplementary Table 1. LM-PCR to detect double-strand signal sequence breaks 3′ of the V γ 5 and V γ 2 gene segments were carried out as described 31,44 using primers listed in Supplementary Table 1.…”

Section: Semi-quantitative Pcr Rt-pcr and Lm-pcrmentioning

confidence: 99%

Interleukin 15 controls the generation of the restricted T cell receptor repertoire of γδ intestinal intraepithelial lymphocytes

2005

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AbstractγδT cells are prevalent in the mucosal epithelia and are postulated to act as sentries to maintain tissue integrity. What these γδT cells recognize is poorly defined, but based on the restricted T cell receptor (TCR) repertoire, the notion that they are selected by self-antigens of low complexity has been widely disseminated. We present data demonstrating that generation of the restricted TCR Vγ gene repertoire of intestinal intraepithelial lymphocytes is regulated by IL-15, which induces Vγ gene segmentspecific local chromatin modifications and enhanced accessibility conducive for subsequent targeted gene rearrangement. This cytokine-directed tissue-specific TCR repertoire formation likely reflects distinct TCR repertoire selection criteria for γδ and αβT cell lineages adopted for different antigen recognition strategies.Intestinal intraepithelial lymphocytes (i-IELs) found within the intestinal epithelial layer are an essential component of mucosal immunity. Similar to T cell subsets in other lymphoid tissues, i-IELs are composed of two T cell types, αβ and γδT cells. In contrast to other tissues, however, γδT cells are prevalent in the mucosal epithelia of most vertebrates and are thought to be a major source of secreted factors necessary for the maintenance of tissue integrity subsequent to infection, transformation, or cell injury 1-3 .Despite the long history of i-IELs, their origin and ligand specificity remain uncertain. Earlier work has indicated that αβ i-IELs originate exclusively from the thymus in normal mice 4 , but whether γδ i-IELs are subject to similar developmental constraints is unclear. The majority of human and mouse γδ i-IELs express the homodimeric αα form of the CD8 coreceptor and exhibit restricted Variable (V) γ and V δ gene usage. In C57BL/6 (B6) mice, for example, V γ 5 expressing cells constitute the predominant i-IEL population in the small intestine [5][6][7] . Mouse strain-specific preferential usage of Tcrg and Tcrd genes among i-IELs arises from complex molecular and cellular controls with evidence for genetic linkage to the Tcrg, Tcrd and H2 loci 6,8,9 , but the exact mechanism is unknown. Two non-mutually exclusive mechanistic processes can be considered to account for the restricted TCR gene usage: cellular selection and programmed TCR gene rearrangement. A hallmark of adaptive immunity is the cellular selection process geared toward forming a population of cells with antigen receptor repertoires that can recognize the entire external universe of antigens. This selection pressure acts on immature cell subsets expressing randomly generated clonal antigen receptors. Although the TCR-driven selection shaping the αβTCR repertoire of conventional αβT cells constitutes a fundamental theme in immunology, whether a similar process is needed for γδT cell development, and specifically for γδ i-IELs, remains a matter of debate [10][11][12] .

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“…The separated populations were Ͼ90% pure. Nuclei prepared as described (25) from ϳ5 ϫ 10 7 Ly49A Ϫ or Ly49A ϩ cells, were incubated with varying concentrations of DNase I (Sigma-Aldrich, St. Louis, MO) for 5 min at 37°C (25). DNase I HSS in liver chromatin was assayed as described (26).…”

Section: Dnase I Hypersensitivity Assaymentioning

confidence: 99%

Genomic Ly49A Transgenes: Basis of Variegated Ly49A Gene Expression and Identification of a Critical Regulatory Element

Tanamachi

Moniot

Cado

et al. 2004

The Journal of Immunology

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Several gene families are known in which member genes are expressed in variegated patterns in differentiated cell types. Mechanisms responsible for imposition of a variegated pattern of gene expression are unknown. Members of the closely linked Ly49 inhibitory receptor gene family are expressed in a variegated fashion by NK cells. Variegated expression of these genes results in subsets of NK cells that differ in specificity for MHC class I molecules. To address the mechanisms underlying variegation, a 30-kb genomic fragment containing a single Ly49 gene was used to generate a panel of murine transgenic lines. The results demonstrated that, in almost all of the lines, the isolated Ly49A gene was expressed in a variegated pattern, remarkably similar in nearly all respects to the expression pattern of the endogenous Ly49A gene. Furthermore, the developmental timing of gene expression and regulation by host MHC molecules closely mirrored that of the endogenous Ly49A gene. Therefore, Ly49 variegation does not require competition in cis between different Ly49 genes, and the sequences imposing variegation are located proximally to Ly49 genes. Efforts to define regulatory elements of the Ly49A gene led to the identification of a DNase I hypersensitive site 4.5 kb upstream of the Ly49A gene transcription initiation site, which was shown to be essential for transgene expression. Highly related sequence elements were found upstream of other Ly49 genes, suggesting that a similar regulatory element controls each Ly49 gene.

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A Novel Element Upstream of the Vγ2 Gene in the Murine T Cell Receptor γ Locus Cooperates with the 3′ Enhancer to Act as a Locus Control Region

Cited by 27 publications

References 49 publications

Induction of Germline Transcription in the Human TCRγ Locus by STAT5

Induction of Germline Transcription in the Human TCRγ Locus by STAT5

Interleukin 15 controls the generation of the restricted T cell receptor repertoire of γδ intestinal intraepithelial lymphocytes

Genomic Ly49A Transgenes: Basis of Variegated Ly49A Gene Expression and Identification of a Critical Regulatory Element

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