Activation of the TCR Complex by Peptide-MHC and Superantigens

Louis-Dit-Sully, Christine; Blumenthal, Britta; Duchniewicz, Marlena; Beck-García, Katharina; Fiala, Gina J.; Beck-García, Esmeralda; Mukenhirn, Markus; Minguet, Susana; Schamel, Wolfgang W. A.

doi:10.1007/978-3-0348-0726-5_2

Cited by 5 publications

(3 citation statements)

References 60 publications

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“…These mechanisms include the expression of ligands which bind to inhibitory receptors expressed on T cells and suppressing the function of T cell stimulatory receptors, such as T-cell receptor (TCR)/CD3 and CD28 (3,4). In general, T cells are activated by the interaction of the TCR/CD3 complex with an antigen and co-activation of CD28 (5). Co-stimulation of the TCR with CD28 and an antigen promotes the initial phosphorylation events of signal transduction from the TCR and enhances immune support functions (6).…”

Section: Introductionmentioning

confidence: 99%

PD‑L1 expression levels on tumor cells affect their immunosuppressive activity

Yang

Fang

2019

Oncol Lett

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Programmed cell death 1 (PD-1) is an immuno-checkpoint receptor which is primarily expressed on T cells, monocytes, natural killer cells and macrophages. Programmed death-ligand 1 (PD-L1) is the primary ligand of PD-1 and is constitutively expressed on antigen presenting cells, mesenchymal stem cells and bone marrow-derived mast cells. In addition, PD-L1 is also expressed on a wide range of tumor cells, including lung cancer, breast cancer and melanoma. PD-1 and PD-L1 are important members of the immunoglobulin super-family and participate in immune regulation. In the present study, the immune-suppressive effects of a number of tumor cell lines were determined. The breast tumor cell lines MCF-7 and MDA-MB-231 displayed the largest inhibitory effects on T-cell activation and cytokine secretion in a co-culture system. The HepG2, A549 and A375 cells displayed limited inhibitory effects. MCF-7 and MDA-MB-231 cells expressed the highest level of PD-L1 among the cells used, which may explain their higher immuno-suppressive effects. Compound A0-L, a small molecule inhibitor of the PD-1/PD-L1 interaction, restored T cell functions. Additionally, it was demonstrated that the tumor cells with higher levels of PD-L1 expression suppressed signaling pathways involved in T-cell activation, such as the T-cell receptor- zeta chain of T cell receptor associated protein kinase ZAP70-RAS-GTPase-extracellular-signal-regulated kinases and CD28-PI3K-Akt serine/threonine kinases pathways. These findings suggest that tumor cells with higher expression levels of PD-L1 may exhibit higher immuno-suppressive activity, and that drugs targeting the PD-1/PD-L1 interaction may have improved therapeutic effects on tumors expressing higher levels of PD-L1.

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Section: Introductionmentioning

confidence: 99%

PD‑L1 expression levels on tumor cells affect their immunosuppressive activity

Yang

Fang

2019

Oncol Lett

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“…On the basis of biological, structural, and computational data, a multitude of models have been proposed to define the mechanism of TCR triggering upon pMHC binding. Strikingly, many of the models consider TCR clustering and/or alterations of the quaternary structure of the TCR–CD3 complex as a prerequisite for T-cell activation. , The overall structural organization of the TCR–CD3 complex and the underlying molecular mechanism in early T-cell triggering that results in the exposure of intracellular CD3 phosphorylation motifs, however, remain unclear. , …”

mentioning

confidence: 99%

“…Strikingly, many of the models consider TCR clustering and/or alterations of the quaternary structure of the TCR−CD3 complex as a prerequisite for T-cell activation. 28,29 The overall structural organization of the TCR−CD3 complex and the underlying molecular mechanism in early T-cell triggering that results in the exposure of intracellular CD3 phosphorylation motifs, however, remain unclear. 30,31 A potential role for the TCR Cα domain in early T-cell triggering has been discussed extensively in the literature.…”

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confidence: 99%

The T-Cell Receptor Can Bind to the Peptide-Bound Major Histocompatibility Complex and Uncomplexed β₂-Microglobulin through Distinct Binding Sites

et al. 2017

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T-Cell receptor (TCR)-mediated recognition of the peptide-bound major histocompatibility complex (pMHC) initiates an adaptive immune response against antigen-presenting target cells. The recognition events take place at the TCR-pMHC interface, and their effects on TCR conformation and dynamics are controversial. Here, we have measured the time-resolved hydrogen/deuterium exchange (HDX) of a soluble TCR in the presence and absence of its cognate pMHC by mass spectrometry to delineate the impact of pMHC binding on solution-phase structural dynamics in the TCR. Our results demonstrate that while TCR-pMHC complex formation significantly stabilizes distinct CDR loops of the TCR, it does not trigger structural changes in receptor segments remote from the binding interface. Intriguingly, our HDX measurements reveal that the TCR α-constant domain (C- and F-strand) directly interacts with the unbound MHC light chain, β-microglobulin (βm). Surface plasmon resonance measurements corroborated a binding event between TCR and βm with a dissociation constant of 167 ± 20 μM. We propose a model structure for the TCR-βm complex based on a refined protein-protein docking approach driven by HDX data and information from molecular dynamics simulations. Using a biological assay based on TCR gene-engineered primary human T cells, we did not observe a significant effect of βm on T-cell cytotoxicity, suggesting an alternate role for βm binding. Overall, we show that binding of βm to the TCR occurs in vitro and, as such, not only should be considered in structure-function studies of the TCR-pMHC complex but also could play a hitherto unidentified role in T-cell function in vivo.

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PD-1/PD-L1 affects Graves progression through lymphocytes on the proliferation, apoptosis and inflammatory cytokine secretion of thyroid follicular epithelial cells

Han

Huang

et al. 2020

J. Toxicol. Sci.

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Activation of the TCR Complex by Peptide-MHC and Superantigens

Cited by 5 publications

References 60 publications

PD‑L1 expression levels on tumor cells affect their immunosuppressive activity

PD‑L1 expression levels on tumor cells affect their immunosuppressive activity

The T-Cell Receptor Can Bind to the Peptide-Bound Major Histocompatibility Complex and Uncomplexed β₂-Microglobulin through Distinct Binding Sites

PD-1/PD-L1 affects Graves progression through lymphocytes on the proliferation, apoptosis and inflammatory cytokine secretion of thyroid follicular epithelial cells

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Activation of the TCR Complex by Peptide-MHC and Superantigens

Cited by 5 publications

References 60 publications

PD‑L1 expression levels on tumor cells affect their immunosuppressive activity

PD‑L1 expression levels on tumor cells affect their immunosuppressive activity

The T-Cell Receptor Can Bind to the Peptide-Bound Major Histocompatibility Complex and Uncomplexed β2-Microglobulin through Distinct Binding Sites

PD-1/PD-L1 affects Graves progression through lymphocytes on the proliferation, apoptosis and inflammatory cytokine secretion of thyroid follicular epithelial cells

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The T-Cell Receptor Can Bind to the Peptide-Bound Major Histocompatibility Complex and Uncomplexed β₂-Microglobulin through Distinct Binding Sites