Transcriptional regulation of lymphocyte lineage commitment

Rothenberg, Ellen V.; Telfer, Janice C.; Anderson, Michael

doi:10.1002/(sici)1521-1878(199909)21:9<726::aid-bies4>3.0.co;2-s

Cited by 41 publications

(26 citation statements)

References 127 publications

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“…During the expansion of thymic T cell progenitors, differentiation proceeds accompanying loss of NK potential [21] and dendritic cell potential [42]. A variety of molecules participating in the cell interaction and intracellular process during the early stages of T cell development are becoming clarified [43][44][45]. Detailed illustration of the cellular processes as revealed in the present study in combination with the molecular analysis will facilitate the clarification of early events in thymic T cell development.…”

Section: Discussionmentioning

confidence: 67%

Extensive proliferation of T cell lineage‐restricted progenitors in the thymus: an essential process for clonal expression of diverse T cell receptor β chains

et al. 2003

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For clonal diversification of TCR, a large number of T cell progenitors are required in which highly diverse TCR g chains are accommodated individually. In the present study, we examined the proliferative potential of thymic progenitors that have been defined to be T cell lineage restricted. We show that the earliest fetal thymus (FT) cells from Rag2 -/-mice, when cultured individually in a thymic organ culture system, produced 150-1,800 CD25 + cells. Since differentiation and proliferation of Rag2 -/-thymocytes are arrested at the stage of TCR g chain gene rearrangement, the observed proliferation was considered to represent the proliferative potential of progenitors prior to the TCR g rearrangement. A comparable level of proliferation was revealed to occur by analyzing the D g -J g rearrangement profiles of T cells generated from single progenitors in the earliest population of FT from normal mice. The proliferative potential of progenitors declined along with the progression of developmental stages. Such an extensive proliferation of progenitors after the restriction to the T cell lineage may be an essential process ensuring the clonal diversification of TCR g chains.

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Section: Discussionmentioning

confidence: 67%

Extensive proliferation of T cell lineage‐restricted progenitors in the thymus: an essential process for clonal expression of diverse T cell receptor β chains

et al. 2003

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“…Because of the lack of recombinase, the TCR gene remains in germline configuration in these cells, with the C␤ enhancer hundreds of kilobases away. Although the Rag2 Ϫ/Ϫ thymocytes are arrested as immature cells, they do reach a stage of development when normal thymocytes have become committed to the T cell lineage and are fully capable of transcribing the TCR␤-chain gene (3)(4)(5)(6). In this context, the basal levels of "germline" transcription from unrearranged V␤ segments can be measured sensitively.…”

Section: T He Differentiation and Maturation Of T Cells Depends On Thmentioning

confidence: 99%

Differential Transcriptional Regulation of Individual TCR Vβ Segments Before Gene Rearrangement

Chen

Rowen

Hood

et al. 2001

The Journal of Immunology

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The promoter sequences of individual murine TCR Vβ segments are dissimilar, but any functional differences between them are masked after productive gene rearrangement by the dominance of the TCRβ 3′ enhancer. However, thymocytes of recombination-activating gene-2 (Rag2)-deficient mice allow the transcriptional activity of Vβ promoters to be studied before rearrangement. Here we report that many Vβ segments are detectably transcribed in Rag2−/− thymocytes and that there are significant differences in expression among different Vβ segments. Primer extension and characterization of cDNA clones from SCID thymocytes suggest that these germline Vβ transcripts generally use the same start sites as those previously determined in mature T cells. The strength of expression before rearrangement does not correlate with proximity to the known enhancer, because members of the most distal Vβ cluster (Vβ2.1, Vβ1.1, Vβ4.1) are relatively strongly expressed and more proximal Vβ segments (Vβ14.1, Vβ3.1, Vβ7.1, Vβ6.1) are only weakly expressed. Different Vβ segments also show different developmental programs of activation in different thymocyte subsets, with the Vβ5.1(L)-8.2(V) spliced transcript expressed earliest as well as most strongly overall. Comparison with Rag+ MHC class I−/− and class II−/− thymocytes confirms that many of these expression differences are leveled by rearrangement and/or by β selection, before MHC-dependent selection. However, the expression pattern of Vβ2.1 is highly distinctive and includes cell types apparently outside the T lineage, suggesting potential acquisition of specialized roles.

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“…GFP-expressing thymocytes from these mice could then be identified by four-color flow cytometry, using Sca-1 (Ly6-A/E) and HSA (CD24) expression for primary subdivision of cell types (reviewed in Ref. 28), as shown in Fig. 7.…”

Section: Il-2 Is Spontaneously Induced Both In Tcrmentioning

confidence: 99%

“…These two populations express IL-2 mRNA in vivo and are thought to represent pluripotent precursors and NK-like cells, respectively (28). GFP ϩ cells constituted a fraction of each of these subsets: 25-30% of the Sca-1 ϩ HSA low subset and …”

Section: Il-2 Is Spontaneously Induced Both In Tcrmentioning

confidence: 99%

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A New Regulatory Region of the IL-2 Locus That Confers Position-Independent Transgene Expression

Yui

Hernández-Hoyos

Rothenberg

2001

The Journal of Immunology

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Although the promoter/enhancer of the IL-2 gene mediates inducible reporter gene expression in vitro, it cannot drive consistent expression in transgenic mice. The location and existence of any regulatory elements that could open the IL-2 locus in vivo have remained unknown, preventing analysis of IL-2 regulation in developmental contexts. In this study, we report the identification of such a regulatory region, marked by novel DNase-hypersensitive sites upstream of the murine IL-2 promoter in unstimulated and stimulated T cells. Inclusion of most of these sites in an 8.4-kb IL-2 promoter green fluorescent protein transgene gives locus control region-like activity. Expression is efficient, tissue specific, and position independent. This transgene is expressed not only in peripheral T cells, but also in immature thymocytes and thymocytes undergoing positive selection, in agreement with endogenous IL-2 expression. In contrast, a 2-kb promoter green fluorescent protein transgene, lacking the new hypersensitive sites, is expressed in only a few founder lines, and expression is dysregulated in CD8+ cells. Thus, the 6.4 kb of additional upstream IL-2 sequence contains regulatory elements that provide integration site independence and differential regulation of transgene expression in CD8 vs CD4 cells.

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Transcriptional regulation of lymphocyte lineage commitment

Cited by 41 publications

References 127 publications

Extensive proliferation of T cell lineage‐restricted progenitors in the thymus: an essential process for clonal expression of diverse T cell receptor β chains

Extensive proliferation of T cell lineage‐restricted progenitors in the thymus: an essential process for clonal expression of diverse T cell receptor β chains

Differential Transcriptional Regulation of Individual TCR Vβ Segments Before Gene Rearrangement

A New Regulatory Region of the IL-2 Locus That Confers Position-Independent Transgene Expression

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