Anti-CD3 Fab Fragments Enhance Tumor Killing by Human γδ T Cells Independent of Nck Recruitment to the γδ T Cell Antigen Receptor

Juraske, Claudia; Wipa, Piyamaporn; Morath, Anna; Hidalgo, José Villacorta; Hartl, Frederike A.; Raute, Katrin; Oberg, Hans‐Heinrich; Wesch, Daniela; Fisch, Paul; Minguet, Susana; Pongcharoen, Sutatip; Schamel, Wolfgang W. A.

doi:10.3389/fimmu.2018.01579

Cited by 23 publications

(19 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This potential binding stimulates the γδ TCR, but without stabilizing the γδ TCR in its active CD3 conformation [57]. Recruitment of Nck (non‐catalytic region of tyrosine kinase adaptor protein 1) is necessary for the activation of the γδ T cells in the presence of the CD3 antibody, which is not observed with pAg stimulation of γδ T cells [50]. It appears that the BTN expression plays an important role in dictating the IL‐17 versus IFN‐γ dichotomy and explains the increased IL‐17 production following CD3 ligation, which is not observed with HDMAPP.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia regulates the differentiation and anti-tumor effector functions of γδT cells in oral cancer

Sureshbabu

Chaukar

Chiplunkar

2020

Clinical and Experimental Immunology

View full text Add to dashboard Cite

Summary Hypoxia within the tumor microenvironment (TME) is a key factor contributing to immunosuppression in tumors, co‐relating with poor treatment outcome and decreased overall survival in advanced oral cancer (OC) patients. Vδ2 is a dominant subset of gamma delta T cells (γδT cells) present in the peripheral blood which exhibits potent anti‐tumor cytotoxicity and is evolving as a key player of anti‐cancer cellular therapy. However, the fate of γδT cells in hypoxic oral tumors remains elusive. In the present study, we compared the effect of hypoxia (1% O2) and normoxia (21% O2) on the expansion, proliferation, activation status, cytokine secretion and cytotoxicity of γδT cells isolated from OC patients and healthy individuals. Hypoxia‐exposed γδT cells exhibited reduced cytotoxicity against oral tumor cells. Our data demonstrated that hypoxia reduces the calcium efflux and the expression of degranulation marker CD107a in γδT cells, which explains the decreased anti‐tumor cytotoxicity of γδT cells observed under hypoxia. Hypoxia‐exposed γδT cells differentiated to γδT17 [γδ T cells that produce interleukin (IL)‐17] cells, which corroborated our observations of increased γδT17 cells observed in the oral tumors. Co‐culture of γδT cells with CD8 T cells in the presence of hypoxia showed that programmed cell death ligand 1 (PD‐L1)high γδT cells brought about apoptosis of programmed cell death 1 (PD‐1)high CD8 T cells which could be significantly reversed upon blocking PD‐1. Thus, future immunotherapeutic treatment modality for oral cancer may use a combined approach of blocking the PD‐1/PD‐L1 signaling and targeting hypoxia‐inducible factor 1α, which may help in reversing hypoxia‐induced immunosuppression.

show abstract

Section: Discussionmentioning

confidence: 99%

Hypoxia regulates the differentiation and anti-tumor effector functions of γδT cells in oral cancer

Sureshbabu

Chaukar

Chiplunkar

2020

Clinical and Experimental Immunology

View full text Add to dashboard Cite

show abstract

“…This indicates that the enhancing effect on tumor killing is dependent on CD3ε PRS exposure. A similar enhancing effect on tumor killing can be induced by Fab fragments of the anti‐CD3ε Abs . This has the advantage that anti‐CD3ε Fab fragments alone do not activate the Vγ9Vδ2 T cells but increase the effector functions in the presence of the target cells.…”

Section: Anti‐cd3ε Ab‐induced Rearrangements At the γδ Tcr And Translmentioning

confidence: 90%

αβ and γδ T cell receptors: Similar but different

Morath

Schamel

2020

Journal of Leukocyte Biology

Self Cite

View full text Add to dashboard Cite

There are 2 populations of T lymphocytes, αβ T and γδ T cells, that can be distinguished by the expression of either an αβ TCR or a γδ TCR, respectively. Pairing of the Ag binding heterodimer, which consists of TCR‐α/TCR‐β (TCRαβ) or TCR‐γ/TCR‐δ (TCRγδ), with proteins of the CD3 complex forms the complete αβ or γδ TCR. Despite some similarities in the structure of TCRαβ and TCRγδ and the shared subunits of the CD3 complex, the 2 receptors differ in important aspects. These include the assembly geometry of the complex, the glycosylation pattern, the plasma membrane organization, as well as the accessibility of signaling motifs in the CD3 intracellular tails. These differences are reflected in the different demands and outcomes of ligand‐induced signaling. It was shown that exposure of the proline‐rich sequence (PRS) in CD3ε occurs with all activating αβ TCR ligands and is required to induce αβ TCR signaling. In sharp contrast, CD3ε PRS exposure was not induced by binding of those ligands to the γδ TCR that have been studied. Further, signaling by the γδ TCR occurs independently of CD3ε PRS exposure. Interestingly, it can be enhanced by anti‐CD3ε Ab‐induced enforcement of CD3ε PRS exposure. This review contrasts these two similar, but different immune receptors.

show abstract

“…For the sake of simplicity, this review focuses on the αβ TCR and not on the pre‐TCR or the γδ TCR. Of note, the γδ TCR also uses CD3 and ζ to relay the signal of ligand binding into the cell, however, it functions in a different manner and thus, the mechanisms discussed here about the αβ TCR cannot be extrapolated to the γδ TCR.…”

Section: Tcr Triggering Modelsmentioning

confidence: 98%

The TCR is an allosterically regulated macromolecular machinery changing its conformation while working

Schamel

Alarcón

Minguet

2019

Immunological Reviews

Self Cite

View full text Add to dashboard Cite

The αβ T‐cell receptor (TCR) is a multiprotein complex controlling the activation of T cells. Although the structure of the complete TCR is not known, cumulative evidence supports that the TCR cycles between different conformational states that are promoted either by thermal motion or by force. These structural transitions determine whether the TCR engages intracellular effectors or not, regulating TCR phosphorylation and signaling. As for other membrane receptors, ligand binding selects and stabilizes the TCR in active conformations, and/or switches the TCR to activating states that were not visited before ligand engagement. Here we review the main models of TCR allostery, that is, ligand binding at TCRαβ changes the structure at CD3 and ζ. (a) The ITAM and proline‐rich sequence exposure model, in which the TCR's cytoplasmic tails shield each other and ligand binding exposes them for phosphorylation. (b) The membrane‐ITAM model, in which the CD3ε and ζ tails are sequestered inside the membrane and again ligand binding exposes them. (c) The mechanosensor model in which ligand binding exerts force on the TCR, inducing structural changes that allow signaling. Since these models are complementary rather than competing, we propose a unified model that aims to incorporate all existing data.

show abstract

Anti-CD3 Fab Fragments Enhance Tumor Killing by Human γδ T Cells Independent of Nck Recruitment to the γδ T Cell Antigen Receptor

Cited by 23 publications

References 60 publications

Hypoxia regulates the differentiation and anti-tumor effector functions of γδT cells in oral cancer

Hypoxia regulates the differentiation and anti-tumor effector functions of γδT cells in oral cancer

αβ and γδ T cell receptors: Similar but different

The TCR is an allosterically regulated macromolecular machinery changing its conformation while working

Contact Info

Product

Resources

About