Productive T-cell receptor beta-chain gene rearrangement: coincident regulation of cell cycle and clonality during development in vivo.

Hoffman, Eva A.; Passoni, Lorena; Crompton, Tessa; Leu, Thomas; Schatz, David G.; Koff, Andrew; Owen, Michael John; Hayday, Adrian

doi:10.1101/gad.10.8.948

Cited by 299 publications

(280 citation statements)

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“…The CD4 and CD8 double negative (DN) 3 cell subset that represents 1-5% of the total thymocytes includes mature CD3-positive cells (mostly ␥␦ T cells) as well as at least four immature thymocyte subsets that can be distinguished based on surface expression of CD44 (Pgp-1), CD25 (IL-2R␣), and CD117 (c-kit). The CD117 Ϫ CD44 Ϫ CD25 ϩ DN stage is a critical step for T cell differentiation during which productive TCR␤ gene rearrangements are generated (2). Once this step has occurred, the TCR␤ protein covalently associates with the pT␣ chain and subunits of the CD3 complex to form the pre-TCR (3).…”

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confidence: 99%

Transgenic Expression of the p16INK4a Cyclin-Dependent Kinase Inhibitor Leads to Enhanced Apoptosis and Differentiation Arrest of CD4−CD8− Immature Thymocytes

Lagresle-Peyrou

Gardie

Eyquem

et al. 2002

The Journal of Immunology

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In the thymus, T cell development proceeds by successive steps of differentiation, expansion, and selection. Control of thymocyte proliferation is critical to insure the full function of the immune system and to prevent T cells from transformation. Deletion of the cell cycle inhibitor p16INK4a is frequently observed in human T cell neoplasias and, in mice, gene targeted inactivation of the Ink4a locus enhances thymocyte expansion and predisposes mutant animal to tumorigenesis. Here, we investigate the mechanism by which p16Ink4a controls thymocyte development by analyzing transgenic mice expressing the human p16INK4a into the T cell lineage. We show that forced expression of p16INK4a in thymocytes blocked T cell differentiation at the early CD4−CD8−CD3−CD25+ stage without significantly affecting the development of γδ T cells. Pre-TCR function was mimicked by the induction of CD3 signaling in thymocytes of recombinase activating gene (RAG)-2-deficient mice (RAG-2−/−). Upon anti-CD3ε treatment in vivo, p16INK4a-expressing RAG-2−/− thymocytes were not rescued from apoptosis, nor could they differentiate. Our data demonstrate that expression of p16INK4a prevents the pre-TCR-mediated expansion and/or survival of differentiating thymocytes.

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confidence: 99%

Transgenic Expression of the p16INK4a Cyclin-Dependent Kinase Inhibitor Leads to Enhanced Apoptosis and Differentiation Arrest of CD4−CD8− Immature Thymocytes

Lagresle-Peyrou

Gardie

Eyquem

et al. 2002

The Journal of Immunology

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“…In the transition from double-negative (DN) 3 to double-positive (DP) thymocytes, the quality of the ␤-chain rearrangement product is controlled by its ability to pair with the pre-T ␣-chain (1). This occurs in the CD44 Ϫ compartment of DN mouse thymocytes (2,3) and is referred to as ␤ selection (4). The subset of DN cells in which the ␤-chain is selected in man is not known, although recent data have implicated the CD4 ϩ CD3 Ϫ CD8 Ϫ immature single-positive (ISP) cells (5).…”

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confidence: 99%

Thymocyte Maturation: Selection for In-Frame TCR α-Chain Rearrangement Is Followed by Selection for Shorter TCR β-Chain Complementarity-Determining Region 3

Yassai

Gorski

2000

The Journal of Immunology

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Thymocyte maturation consists of a number of stages, the goal of which is the production of functioning T cells that respond to foreign antigenic peptides using their clonotypic receptors. Selection of a productively rearranged TCR β-chain is the first stage in the process and occurs at the double-negative to double-positive (DP) transition. Later maturation stages are based on changes in markers such as CD5, CD69, or IL-7R. A stage in which α-chains are selected has also been identified using β-chain transgenic mice. Here we identify two additional selection stages in human thymocytes based on characteristics of the TCR. α selection is measured directly by identification of in-frame rearrangements and is associated with the appearance of CD3 on the DP thymocyte surface. The next stage has not yet been described and involves selection of thymocytes that express shorter TCR β-chain complementarity-determining region 3 (CDR3). This stage is associated with the acquisition of high levels of CDR3 by DP cells and the transition to SP thymocytes. The extent of CDR3 length selection observed is a function of the TCR V and J genes. We propose that CDR3 length selection is based on recognition of the MHC. Thus, there exist limitations on the allowable length of that portion of the TCR most intimately in contact with MHC and peptide. This may be a physical representation of positive selection.

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“…In this context, our data with TCRb Tg mice as well as other results with DN3 thymocytes from normal mice [1] clearly implicate pTa as being required for allelic exclusion. Possible consequences of pre-TCR signaling that might regulate allelic exclusion include modifications in chromatin accessibility [30] or contraction [31] at the TCRb locus itself as well as changes in the expression [32] or stability [26] of the RAG proteins. With regard to the latter point, our failure to observe down-regulation of RAG1 mRNA or RAG2 protein expression in DN3 thymocytes in the presence of a TCRb transgene does not support a direct role for pre-TCR signaling in the regulation of RAG expression.…”

Section: Discussionmentioning

confidence: 99%

A critical lineage‐nonspecific role for pTα in mediating allelic and isotypic exclusion in TCRβ‐transgenic mice

Ferrero¹,

Grosjean²,

Fiorini³

et al. 2007

Eur J Immunol

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Although it is well established that early expression of TCRb transgenes in the thymus leads to efficient inhibition of both endogenous TCRb and TCRc rearrangement (also known as allelic and "isotypic" exclusion, respectively) the role of pTa in these processes remains controversial. Here, we have systematically re-evaluated this issue using three independent strains of TCRb-transgenic mice that differ widely in transgene expression levels, and a sensitive intracellular staining assay that detects endogenous TCRVb expression in individual immature thymocytes. In the absence of pTa, both allelic and isotypic exclusion were reversed in all three TCRb-transgenic strains, clearly demonstrating a general requirement for pre-TCR signaling in the inhibition of endogenous TCRb and TCRc rearrangement. Both allelic and isotypic exclusion were pTa dose dependent when transgenic TCRb levels were subphysiological. Moreover, pTa-dependent allelic and isotypic exclusion occurred in both ab and cd T cell lineages, indicating that pre-TCR signaling can potentially be functional in cd precursors. Finally, levels of endogenous RAG1 and RAG2 were not down-regulated in TCRb-transgenic immature thymocytes undergoing allelic or isotypic exclusion. Collectively, our data reveal a critical but lineage-nonspecific role for pTa in mediating both allelic and isotypic exclusion in TCRb-transgenic mice. IntroductionT cells can be divided into ab and cd lineages based on their expression of TCRab or TCRcd. During development in the thymus, ab and cd lineages separate at an early CD4 -CD8 -double-negative (DN) stage, but the precise mechanism of lineage divergence remains controversial.One molecule that has been postulated to play a key role in ab/cd lineage commitment is the pTa chain. pTa is a critical component of the pre-TCR which consists, in addition, of a functionally rearranged TCRb chain and CD3 signaling components. Signaling through the pre-TCR has been reported to be responsible for many important functions during the development of ab lineage cells, including TCRb allelic exclusion [1-3], TCRc silencing [4], and extensive proliferation during the transition from DN to CD4 + CD8 + double-positive (DP) stages [5]. Since pTa -/-mice have an increased number of cd cells that harbor an increased frequency of in-frame TCRb rearrangements [6], it has also been proposed that the pre-TCR favors ab lineage commitment at the expense of cd cells [6]. Since functions of pTa are often difficult to study in normal mice, several groups have crossed pTa-deficient mice with TCRb-transgenic (Tg) mice to assess various putative roles for the pre-TCR during thymus development [7,8]. However, the results of these studies are in many cases controversial and it is still not known whether transgenic "artifacts" caused by overexpression or premature expression of the transgenic TCRb chain may obscure the contribution of pTa to the observed phenotypes.In order to re-evaluate this issue in a systematic manner, we have utilized three independent TCRb Tg mouse...

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Productive T-cell receptor beta-chain gene rearrangement: coincident regulation of cell cycle and clonality during development in vivo.

Cited by 299 publications

References 50 publications

Transgenic Expression of the p16INK4a Cyclin-Dependent Kinase Inhibitor Leads to Enhanced Apoptosis and Differentiation Arrest of CD4−CD8− Immature Thymocytes

Transgenic Expression of the p16INK4a Cyclin-Dependent Kinase Inhibitor Leads to Enhanced Apoptosis and Differentiation Arrest of CD4−CD8− Immature Thymocytes

Thymocyte Maturation: Selection for In-Frame TCR α-Chain Rearrangement Is Followed by Selection for Shorter TCR β-Chain Complementarity-Determining Region 3

A critical lineage‐nonspecific role for pTα in mediating allelic and isotypic exclusion in TCRβ‐transgenic mice

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