On the Dynamics of TCR:CD3 Complex Cell Surface Expression and Downmodulation

Liu, Haiyan; Rhodes, Michele; Wiest, David L.; Vignali, Dario A.A.

doi:10.1016/s1074-7613(00)00066-2

Cited by 339 publications

(390 citation statements)

References 64 publications

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“…In physiological T-cell activation, the activation efficiency correlates with the T-cell receptor (TCR) avidity to the cognate peptide-major histocompatibility complex (MHC) complex. [14][15][16][17][18] Optimal CD28 costimulation is provided by high-avidity engagement by dimeric B7.1 expressed on APCs, followed by dimer dissociation that facilitates downregulaton of CD28 and B7.1 internalization. 19 CD28 costimulation induces at least two independent activation pathways: one is integrated with TCR signalling in the context of synapse formation and is mediated through transcriptional enhancement and the second is mediated through increasing mRNA stability.…”

Section: Introductionmentioning

confidence: 99%

CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack

2010

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Adoptive immunotherapy of cancer using chimeric antigen receptor (CAR)-engineered T cells with redirected specificity showed efficacy in recent trials. In preclinical models, 'second-generation' CARs with CD28 costimulatory domain in addition to CD3z performed superior in redirecting T-cell effector functions and survival. Whereas CD28 costimulation sustains physiological T-cell receptor (TCR)-CD3 activation of naïve T cells, the impact of CD28 cosignalling on the threshold of CAR-mediated activation of pre-stimulated T cells without B7-CD28 recruitment remained unclear. Using CARs of different binding affinities, but same epitope specificity, we demonstrate that CD28 cosignalling neither lowered the antigen threshold nor the binding affinity for redirected T-cell activation. 'Affinity ceiling' above which increase in affinity does not increase T-cell activation was not altered. Accordingly, redirected tumor cell killing depended on the binding affinity but was likewise effective for CD3z and CD28-CD3z CARs. In contrast to CD3z, CD28-CD3z CAR-driven activation was not increased further by CD28-B7 engagement. However, CD28 cosignalling, which is required for interleukin-2 induction could not be replaced by high-affinity CD3z CAR binding or high-density antigen engagement. We conclude that CD28 CAR cosignalling does not alter the activation threshold but redirects T-cell effector functions.

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Section: Introductionmentioning

confidence: 99%

CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack

2010

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“…Signal transduction is carried through CD3 that is physically associated to the TCR (10). The CD3-TCR complex is then internalized inducing a significant decrease of membrane CD3/TCR expression and partial activation leads to a non responsiveness status until the membrane level of CD3 is restored (11)(12)(13)(14). A minimal level of TCR/CD3 engagement is required for efficient induction of T cell activation (15)(16)(17).…”

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confidence: 99%

Variability of CD3 membrane expression and T cell activation capacity

Hentati

Gruy

Iobagiu

et al. 2009

Cytometry Part B Clinical

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Background: abT cells have a wide distribution of CD3 membrane density. The aim of this article was to evaluate the significance of the CD3 differential expression on T cell subsets. Analysis was performed on healthy donors and renal transplant patients by flow cytometry. The results obtained are: (1) CD3 expression was widely distributed (CV 5 38.3 6 3.1 to 43 6 2.3%). (2) The CD4, CD8, CD45 and forward scatter were similarly distributed. (3) The diversity of CD3 expression was directly related to the clonotypes: c9, non c9 from cdT cells and Vb clonotype from abT cells (e.g., Vb3FITC 7,980 6 1,628 Vb8PE: Vb20-FITC 11,768 6 1,510). (4) Using a computer simulation, we could confirm differential kinetics of T cell activation according to the initial parameters. Finally, in vitro activation was significantly higher on Vb8 and Vb9 (high CD3) compared with Vb2 and Vb3 (low CD3, P 5 0.040-0.0003).

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“…Finally, the selective retention model proposes that the positively selected ␣␤ combination is maintained on the cell surface while the nonselected ␣-chain is down-modulated or retained within the cell (11). Recent evidence indicates that TCR is constitutively endocytosed and recycled to the cell surface, so that down-modulation may instead be a lack of recycling to the cell surface (13).…”

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confidence: 99%

Allelic Exclusion of the TCR α-Chain Is an Active Process Requiring TCR-Mediated Signaling and c-Cbl

Niederberger

Holmberg

Alam

et al. 2003

The Journal of Immunology

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Phenotypic allelic exclusion at the TCRα locus is developmentally regulated in thymocytes. Many immature thymocytes express two cell surface α-chain species. Following positive selection, the vast majority of mature thymocytes and peripheral T cells display a single cell surface α-chain. A posttranslational mechanism occurring at the same time as positive selection and TCR up-regulation leads to this phenotypic allelic exclusion. Different models have been proposed to explain the posttranslational regulation of the α-chain allelic exclusion. In this study, we report that allelic exclusion is not regulated by competition between distinct α-chains for a single β-chain, as proposed by the dueling α-chain model, nor by limiting CD3 ζ-chain in mature TCRhigh thymocytes. Our data instead favor the selective retention model where the positive selection signal through the TCR leads to phenotypic allelic exclusion by specifically maintaining cell surface expression of the selected α-chain while the nonselected α-chain is internalized. The use of inhibitors specific for Lck and/or other Src kinases indicates a role for these protein tyrosine kinases in the signaling events leading to the down-regulation of the nonselectable α-chain. Loss of the ubiquitin ligase/TCR signaling adapter molecule c-Cbl, which is important in TCR down-modulation and is a negative regulator of T cell signaling, leads to increased dual α-chain expression on the cell surface of double-positive thymocytes. Thus, not only is there an important role for TCR signaling in causing α-chain allelic exclusion, but differential ubiquitination by c-Cbl may be an important factor in causing only the nonselected α-chain to be down-modulated.

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On the Dynamics of TCR:CD3 Complex Cell Surface Expression and Downmodulation

Cited by 339 publications

References 64 publications

CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack

CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack

Variability of CD3 membrane expression and T cell activation capacity

Allelic Exclusion of the TCR α-Chain Is an Active Process Requiring TCR-Mediated Signaling and c-Cbl

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