A critical role for the cytoplasmic tail of pTα in T lymphocyte development

Aifantis, Iannis; Borowski, Christine; Gounari, Fotini; Lacorazza, H. Daniel; Nikolich‐Žugich, Janko; Boehmer, Harald von

doi:10.1038/ni779

Cited by 73 publications

(87 citation statements)

References 27 publications

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“…The data presented in this study clearly indicate that preBCR basal signaling events can be initiated in either the lipid raft or nonraft membrane compartments, thereby severing the link between an absolute requirement for localization of the receptor to lipid rafts and the initiation of signal transduction pathways promoting preBCR/BCR-dependent developmental processes. In agreement with these findings, a preT␣ variant that does not localize to lipid rafts is still capable of promoting thymocyte development (22). Although our results do not support an absolute requirement for the preBCR to initiate signals from lipid rafts, it is still possible that compartmentalization into the liquid-ordered and disordered regions of the plasma membrane affects qualitative and/or quantitative aspects of the signals generated.…”

Section: Discussionsupporting

confidence: 82%

Igα/Igβ Complexes Generate Signals for B Cell Development Independent of Selective Plasma Membrane Compartmentalization

Fuentes‐Pananá

Bannish

Voort

et al. 2005

The Journal of Immunology

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Ligand-induced BCR association with detergent-resistant plasma membrane compartments (lipid rafts) has been argued to be essential for initiating and/or sustaining Igα/Igβ-dependent BCR signaling. Because a fraction of the BCR and an even larger fraction of the preBCR associates with lipid rafts in the apparent absence of ligand stimulation, it has been proposed that raft-associated receptor complexes mediate the ligand-independent basal signaling events observed in resting B lineage cells. However, there is no direct evidence that localization of Igα/Igβ-containing complexes to detergent-resistant membrane compartments is absolutely required for the signaling events that drive B cell development. To address these issues we have designed surrogate preBCR/Igα/Igβ complexes that are incapable of ligand-induced aggregation and that are preferentially targeted to either raft or nonraft compartments. An analysis of their ability to promote the preBCR-dependent proB→preB cell transition of murine B cell progenitors revealed that expression of these surrogate receptor complexes at levels that approximate that of the conventional preBCR can drive B cell development in a manner independent of both aggregation and lipid raft localization.

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Section: Discussionsupporting

confidence: 82%

Igα/Igβ Complexes Generate Signals for B Cell Development Independent of Selective Plasma Membrane Compartmentalization

Fuentes‐Pananá

Bannish

Voort

et al. 2005

The Journal of Immunology

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“…In addition, the pre-TCR also commits immature thymocytes to the § g T cell lineage [3,5]. Despite these important functions and the accumulation of data regarding the domain functions of pT § [6][7][8][9][10], its downstream signaling pathway has not been clearly characterized.…”

Section: Introductionmentioning

confidence: 99%

Impact of early expression of TCR α chain on thymocyte development

Huang

Kanagawa

2004

Eur J Immunol

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thymocytes expressing a transgenic T cell receptor (TCR) § chain have decreased capacity to give rise to CD4 + CD8 + thymocytes when compared with wild-type thymocytes. This inefficient CD4 -CD8 -to CD4 + CD8 + maturation is mediated by the transgenic TCR § chain pairing with endogenous TCR g chain but not with endogenous TCR + chain. Comparison between TCR § chain-transgenic mice with or without a functional pre-TCR § (pT § ) chain reveals that the formation of transgenic § /endogenous g TCR on CD4 -CD8 -thymocytes inhibits the formation of pre-TCR, but at the same time mediates CD4 -CD8 -to CD4 + CD8 + maturation in the absence of pre-TCR, albeit inefficiently. These results indicate that § g TCR and pre-TCR provide different signals for thymocyte development. They also suggest that the precise regulation of the sequential rearrangements of TCR g and § loci and the cellular expansion induced by the pre-TCR may both be evolved to ensure the efficient generation of mature § g T cells.

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“…It was suggested that this constitutive signal required the significant cytoplasmic tail featured by pTa and absent in the TCRa chain [5]. However, experiments using a mutant pTa chain lacking the cytoplasmic portion showed only a slight decrease in thymic cellularity (2-3-fold) compared to mice with WT pTa [8,10,11]. Unfortunately, the differences in transgenic pTa expression in these transgenic models meant that the observed transition to the DP stage was either the result of pTa overexpression or of the insignificance of the cytoplasmic tail [12].…”

Section: Introductionmentioning

confidence: 99%

MHC‐restricted T cell receptor signaling is required for αβ TCR replacement of the pre T cell receptor

et al. 2008

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A developmental block is imposed on CD25 + CD44 -thymocytes at the b-selection checkpoint in the absence of the pre T cell receptor (preTCR) a-chain, pTa. Early surface expression of a transgenic ab TCR has been shown to partially circumvent this block, such that thymocytes progress to the CD4 + CD8 + double-positive stage. We wanted to analyze whether a restricting MHC element is required for ab TCR-expressing doublenegative (DN) thymocytes to overcome the developmental block in pTa-deficient animals. We used the HY-I knock-in model that endows thymocytes with ab TCR expression in the DN compartment but has the advantage of physiological expression levels, in contrast to conventional TCR transgenes. On a pTa-deficient background, this HY-I TCR transgene 'rescued' CD25 + CD44 -thymocytes from apoptosis and enabled progression to later differentiation stages. On a non-selecting MHC background, however, pTa-deficient HY-I mice presented a pronounced reduction in numbers of splenocytes and thymocytes when compared to animals of selecting MHC genotype, showing that MHC restriction is necessary to drive HY-TCR-mediated rescue of pTa-deficient thymocytes.

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A critical role for the cytoplasmic tail of pTα in T lymphocyte development

Cited by 73 publications

References 27 publications

Igα/Igβ Complexes Generate Signals for B Cell Development Independent of Selective Plasma Membrane Compartmentalization

Igα/Igβ Complexes Generate Signals for B Cell Development Independent of Selective Plasma Membrane Compartmentalization

Impact of early expression of TCR α chain on thymocyte development

MHC‐restricted T cell receptor signaling is required for αβ TCR replacement of the pre T cell receptor

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