An Essential Developmental Checkpoint for Production of the T Cell Lineage

Ikawa, Tomokatsu; Hirose, Sachiko; Masuda, Kyoko; Kakugawa, Kiyokazu; Satoh, Rumi; Shibano-Satoh, Asako; Kominami, Ryo; Katsura, Yoshiteru; Kawamoto, Hiroshi

doi:10.1126/science.1188995

Cited by 272 publications

(357 citation statements)

References 21 publications

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“…However, its contribution during DN3 to DP transition has so far not been investigated. In fact, we and others have suggested that IL-7 might even inhibit the DN3 to DP transition [4,44]. To validate our hypothesis, we decided to test the effect of IL-7 on the DN3 to DP transition in this culture system.…”

Section: Il-7 Blocks the Notch-induced Dn3 Differentiation But Not Thmentioning

confidence: 85%

The preTCR‐dependent DN3 to DP transition requires Notch signaling, is improved by CXCL12 signaling and is inhibited by IL‐7 signaling

et al. 2011

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The requirement for Notch signaling during T-cell development has been extensively studied. Nevertheless, the developmental stage at which it is required and whether additional signaling pathways are needed are still poorly understood. By using a stromalcell-free culture system, we show that sorted double-negative 3 (DN3) thymocytes only require a Delta-like-4-induced Notch signal to differentiate into double-positive (DP) cells. This differentiation process is preTCR-a dependent. DN3 cells undergo 4-5 proliferation cycles, and the addition of the chemokine CXCL12 improves proliferation. IL-7 blocks the differentiation of DN3 cells to DP cells but not the Notch-induced proliferation of cultured DN3 cells. The impaired differentiation correlates with an inhibition of Rag-2 upregulation. Overall, the in vitro stromal-cell-free culture system presented here also provides a powerful and unique tool for studying the mechanisms involved in the positive and negative selection of T cells.Key words: Delta-like 4 and preTCR . DN3 cells . Double-positive cells . Notch IntroductionTo maintain T lymphopoiesis, progenitor cells from the BM constantly seed the thymus. In transplantation settings, it has been shown that different progenitors can home to the thymus and generate T cells [1][2][3][4][5][6][7][8][9]. However, under physiological conditions the role of each of these progenitors is still unclear. It is generally believed that the so-called thymic seeding precursor (TSP) still has the capability of generating B cells, NK cells, DCs and other myeloid cells [2,5,6,10,11]. Upon receiving the Notch signal, the differentiation potential towards the B-cell lineage of the TSP is rapidly lost [2,10,11], whereas other lineage options are still maintained [2,5,6,10,11]. However, a recent study using an IL-7Ra reporter mouse indicated that the non-T-cell lineage differentiation of these progenitors is not, or only very rarely, occurring under physiologic conditions [12,13].Within the thymus, the earliest thymocytes are characterized by the absence of CD4 and CD8 expression and are therefore called double-negative (DN) cells. Based on the expression of CD25, CD44 and CD117, DN cells can be subdivided into four subpopulations. DN1 cells express high cell surface levels of CD44 and CD117, and are negative for CD25, whereas their DN2 progeny express all three markers [14][15][16]. In vitro, DN1 and DN2 cells still possess the capacity to differentiate into NK cells, DCs and other myeloid cells [5,6,11,17] suggesting that they are not yet restricted to the T-cell lineage. T-cell commitment is achieved at the DN3 stage. However, the mechanisms operating . It is at this stage of development that the rearrangement of the TCR-b chain locus is completed, and the cells are selected for a productive TCR-b chain rearrangement, also known as the b-selection checkpoint [18][19][20]. DN3 cells that have rearranged their TCR-b chain locus unproductively can either differentiate into g/d T cells or will otherwise undergo apoptosis. DN3 cells car...

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Section: Il-7 Blocks the Notch-induced Dn3 Differentiation But Not Thmentioning

confidence: 85%

The preTCR‐dependent DN3 to DP transition requires Notch signaling, is improved by CXCL12 signaling and is inhibited by IL‐7 signaling

et al. 2011

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“…Induction of TCF-1 and GATA-3 promotes survival and proliferation of early double-negative T-cell precursors (DN1 and DN2) (Germar et al 2011;Weber et al 2011). NOTCH1 signaling, TCF-1, GATA-3, and RUNX1, working together at the DN2 stage, up-regulate BCL11B, which further restricts differentiation into the αβ T-cell lineage (Ikawa et al 2010;Kueh et al 2016).…”

Section: Lymphoid Lineage Commitment: An Ikaros Time Outmentioning

confidence: 99%

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

Georgopoulos

2017

Genes Dev.

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Lymphocyte differentiation is set to produce myriad immune effector cells with the ability to respond to multitudinous foreign substances. The uniqueness of this developmental system lies in not only the great diversity of cellular functions that it can generate but also the ability of its differentiation intermediates and mature effector cells to expand upon demand, thereby providing lifelong immunity. Surprisingly, the goals of this developmental system are met by a relatively small group of DNA-binding transcription factors that work in concert to control the timing and magnitude of gene expression and fulfill the demands for cellular specialization, expansion, and maintenance. The cellular and molecular mechanisms through which these lineage-promoting transcription factors operate have been a focus of basic research in immunology. The mechanisms of development discerned in this effort are guiding clinical research on disorders with an immune cell base. Here, I focus on IKAROS, one of the earliest regulators of lymphoid lineage identity and a guardian of lymphocyte homeostasis.

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“…For example, the fate choice between T and NK cell lineages in the thymus was known to take place during the CLP to pro-T cell transition and to be dependent on Notch1 [112]. Careful gene expression analysis of intermediate cell stages allowed three groups to identify the downstream factor Bcl11b as a key mediator of this specification process [113][114][115] .…”

Section: Gene Expression Analysis Of the Cdp Points To "Pdc-priming"mentioning

confidence: 99%

Transcription factor networks in dendritic cell development

Satpathy

Murphy

2011

Seminars in Immunology

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Dendritic cells (DCs) are a heterogeneous population within the mononuclear phagocyte system (MPS) that derive from bone marrow precursors. Commitment and specification of hematopoietic progenitors to the DC lineage is critical for the proper induction of both immunity and tolerance. This review summarizes the important cytokines and transcription factors required for differentiation of the DC lineage as well as further diversification into specific DC subsets. We highlight recent advances in the characterization of immediate DC precursors arising from the common myeloid progenitor (CMP). Particular emphasis is placed on the corresponding temporal expression of relevant factors involved in regulating developmental options.

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An Essential Developmental Checkpoint for Production of the T Cell Lineage

Cited by 272 publications

References 21 publications

The preTCR‐dependent DN3 to DP transition requires Notch signaling, is improved by CXCL12 signaling and is inhibited by IL‐7 signaling

The preTCR‐dependent DN3 to DP transition requires Notch signaling, is improved by CXCL12 signaling and is inhibited by IL‐7 signaling

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

Transcription factor networks in dendritic cell development

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