Crucial role of the pre-T-cell receptor α gene in development of ap but not γδ T cells

Fehling, Hans Jörg; Krotkova, A. P.; Saint‐Ruf, Claude; Boehmer, Harald von

doi:10.1038/375795a0

Cited by 487 publications

(413 citation statements)

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“…3C). During the transition from DN3 to DP cells, the preTCR complex comprising preTa and TCR-b protein plays a crucial role in selecting and amplifying by proliferation of those DN cells that have undergone a complete productive TCR-b rearrangement [18][19][20]. Cytoplasmic TCR-b expression can first be detected in DN3 cells and has been associated with higher CD27 levels [39].…”

Section: The Dn3 To Dn Transition Is Pretcr Dependent and Is Improvedmentioning

confidence: 99%

“…DN3 cells express high levels of CD25 and low levels of both CD44 and CD117 [14][15][16]. 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.…”

Section: Introductionmentioning

confidence: 99%

“…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 carrying a productive TCR-b chain will express it at the cell surface as a complex together with the preTCR-a (preTa) and CD3 thereby forming the so-called preTCR [18][19][20]. Most preTCRs expressing DN3 will differentiate into the a/b T-cell lineage.…”

mentioning

confidence: 99%

“…However, a small proportion might still give rise to g/d T cells as suggested by the finding that about 20% of g/d T cells contain a TCR-b chain capable of forming a preTCR [21][22][23][24]. The vast majority of DN3 cells that express a TCR-b polypeptide will undergo a preTCR-mediated proliferative expansion [18][19][20] and will differentiate into DN4 cells. DN4 cells have lost the expression of CD25, CD44 and CD117 and are the direct precursors of the immature single-positive (ISP) CD8 1 cells [14][15][16].…”

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confidence: 99%

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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: The Dn3 To Dn Transition Is Pretcr Dependent and Is Improvedmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Mice tg N3-IC (Bellavia et al, 2000), pTa À/À (Fehling et al, 1995) and N3-IC/pTa À/À double-mutant (Bellavia et al, 2002) …”

Section: Methodsmentioning

confidence: 99%

Differential subcellular localization regulates c-Cbl E3 ligase activity upon Notch3 protein in T-cell leukemia

et al. 2009

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Notch3 and pT alpha signaling events are essential for T-cell leukemogenesis and characterize murine and human T-cell acute lymphoblastic leukemia. Genetic ablation of pT alpha expression in Notch3 transgenic mice abrogates tumor development, indicating that pT alpha signaling is crucial to the Notch3-mediated leukemogenesis. Here we report a novel direct interaction between Notch3 and pT alpha. This interaction leads to the recruitment and persistence of the E3 ligase protein c-Cbl to the lipid rafts in Notch3-IC transgenic thymocytes. Conversely, deletion of pT alpha in Notch3 transgenic mice leads to cytoplasmic retention of c-Cbl that targets Notch3 protein to the proteasomal-degradative pathway. It appears that protein kinase C theta (PKC theta), by regulating tyrosine and serine phosphorylation of Cbl, is able to control its function. We report here that the increased Notch3-IC degradation correlates with higher levels of c-Cbl tyrosine phosphorylation in Notch3-IC/pT alpha(-/-) double-mutant thymocytes, which also display a decreased PKC theta activity. Our data indicate that pT alpha/pre-T-cell receptor is able to regulate the different subcellular localization of c-Cbl and, by regulating PKC theta activity, is also able to influence its ubiquitin ligase activity upon Notch3 protein. Oncogene (2010) 29, 1463-1474; doi:10.1038/onc.2009.446; published online 7 December 200

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A TCR α chain transgene induces maturation of CD4− CD8− α β+ T cells from γ δ T cell precursors

et al. 1998

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The proportion of CD4- CD8- double-negative (DN) alpha beta T cells is increased both in the thymus and in peripheral lymphoid organs of TCR alpha chain-transgenic mice. In this report we have characterized this T cell population to elucidate its relationship to alpha beta and gamma delta T cells. We show that the transgenic DN cells are phenotypically similar to gamma delta T cells but distinct from DN NK T cells. The precursors of DN cells have neither rearranged endogenous TCR alpha genes nor been negatively selected by the MIsa antigen, suggesting that they originate from a differentiation stage before the onset of TCR alpha chain rearrangements and CD4/CD8 gene expression. Neither in-frame V delta D delta J delta nor V gamma J gamma rearrangements are over-represented in this population. However, since peripheral gamma delta T cells with functional TCR beta gene rearrangements have been depleted in the transgenics, we propose that the transgenic DN population, at least partially, originates from the precursors of those cells. The present data lend support to the view that maturation signals to gamma delta lineage-committed precursors can be delivered via TCR alpha beta heterodimers.

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Crucial role of the pre-T-cell receptor α gene in development of ap but not γδ T cells

Cited by 487 publications

References 20 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

Differential subcellular localization regulates c-Cbl E3 ligase activity upon Notch3 protein in T-cell leukemia

A TCR α chain transgene induces maturation of CD4− CD8− α β+ T cells from γ δ T cell precursors

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