The γδTCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness

Melandri, Daisy; Zlatareva, Iva; Chaleil, Raphaël A. G.; Dart, Robin; Chancellor, Andrew; Nussbaumer, Oliver; Polyakova, Oxana; Roberts, Natalie; Wesch, Daniela; Kabelitz, Dieter; Irving, Peter M; John, Susan; Mansour, Salah; Bates, Paul A.; Vantourout, Pierre; Hayday, Adrian

doi:10.1038/s41590-018-0253-5

Cited by 171 publications

(201 citation statements)

References 59 publications

Supporting

Mentioning

187

Contrasting

Order By: Relevance

“…On the other side, sensory pathways are being discovered which might give additional or alternative therapeutic angles, such as the recently identified MR-1 specific cancer-selective TCR clone [169]. Finally, while there are many hurdles to be jumped, γδ T cells with their high plasticity [27] represent a potential therapeutic option for a significant patient population with solid tumors.…”

Section: Perspectivementioning

confidence: 99%

Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy?

Künkele

Wesch

Oberg

et al. 2020

Cells

Self Cite

View full text Add to dashboard Cite

Cancer therapies based on in vivo stimulation, or on adoptive T cell transfer of Vγ9Vδ2 T cells, have been tested in the past decades but have failed to provide consistent clinical efficacy. New, promising concepts such as γδ Chimeric Antigen Receptor (CAR) -T cells and γδ T-cell engagers are currently under preclinical evaluation. Since the impact of factors, such as the relatively low abundance of γδ T cells within tumor tissue is still under investigation, it remains to be shown whether these effector T cells can provide significant efficacy against solid tumors. Here, we highlight key learnings from the natural role of Vγ9Vδ2 T cells in the elimination of host cells bearing intracellular bacterial agents and we translate these into the setting of tumor therapy. We discuss the availability and relevance of preclinical models as well as currently available tools and knowledge from a drug development perspective. Finally, we compare advantages and disadvantages of existing therapeutic concepts and propose a role for Vγ9Vδ2 T cells in immune-oncology next to Cluster of Differentiation (CD) 3 activating therapies.

show abstract

Section: Perspectivementioning

confidence: 99%

Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy?

Künkele

Wesch

Oberg

et al. 2020

Cells

Self Cite

View full text Add to dashboard Cite

show abstract

“…In particular, EPCR and annexin A2, as well as phosphorylated metabolites of isoprenoid synthesis, were described as serving as self-antigens that indicate cellular stress [5,[11][12][13]. Most importantly, B7 receptor family-like butyrophilin (BTN) and butyrophilin-like (BTNL) molecules have been implied in the development of specific epithelial and circulating γδ T cell subsets [14][15][16][17] and as direct γδ TCRs ligands [18][19][20][21]. Advances in next-generation sequencing (NGS) analysis of human γδ TCR repertoires, together with the recent identification of γδ TCR ligands, shed light on the vast TCR diversity of human γδ T cells, thereby pointing to a complex role in health and disease.…”

mentioning

confidence: 99%

Human γδ TCR Repertoires in Health and Disease

Fichtner

Ravens

Prinz

2020

Cells

View full text Add to dashboard Cite

The T cell receptor (TCR) repertoires of γδ T cells are very different to those of αβ T cells. While the theoretical TCR repertoire diversity of γδ T cells is estimated to exceed the diversity of αβ T cells by far, γδ T cells are still understood as more invariant T cells that only use a limited set of γδ TCRs. Most of our current knowledge of human γδ T cell receptor diversity builds on specific monoclonal antibodies that discriminate between the two major subsets, namely Vδ2+ and Vδ1+ T cells. Of those two subsets, Vδ2+ T cells seem to better fit into a role of innate T cells with semi-invariant TCR usage, as compared to an adaptive-like biology of some Vδ1+ subsets. Yet, this distinction into innate-like Vδ2+ and adaptive-like Vδ1+ γδ T cells does not quite recapitulate the full diversity of γδ T cell subsets, ligands and interaction modes. Here, we review how the recent introduction of high-throughput TCR repertoire sequencing has boosted our knowledge of γδ T cell repertoire diversity beyond Vδ2+ and Vδ1+ T cells. We discuss the current understanding of clonal composition and the dynamics of human γδ TCR repertoires in health and disease.

show abstract

“…S1G). Although it remains to be tested if any of these positively charged amino acids in the framework regions are involved in recognition of the polyanionic ligands, it is interesting to note that germline‐encoded Vγ sequences were recently shown to be involved in recognition of butyrophilin family members by mouse Vγ7 and human Vγ4 TCRs . Results reported here also demonstrate that the amino acid sequences of CDR3 regions impact the strength of spontaneous reactivity.…”

Section: Discussionmentioning

confidence: 62%

Recognition of synthetic polyanionic ligands underlies “spontaneous” reactivity of Vγ1 γδTCRs

Dunst

Glaros

Englmaier

et al. 2020

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Although γδTCRs were discovered more than 30 yr ago, principles of antigen recognition by these receptors remain unclear and the nature of these antigens is largely elusive. Numerous studies reported that T cell hybridomas expressing several Vγ1‐containing TCRs, including the Vγ1Vδ6 TCR of γδNKT cells, spontaneously secrete cytokines. This property was interpreted as recognition of a self‐ligand expressed on the hybridoma cells themselves. Here, we revisited this finding using a recently developed reporter system and live single cell imaging. We confirmed strong spontaneous signaling by Vγ1Vδ6 and related TCRs, but not by TCRs from several other γδ or innate‐like αβ T cells, and demonstrated that both γ and δ chains contributed to this reactivity. Unexpectedly, live single cell imaging showed that activation of this signaling did not require any interaction between cells. Further investigation revealed that the signaling is instead activated by interaction with negatively charged surfaces abundantly present under regular cell culture conditions and was abrogated when noncharged cell culture vessels were used. This mode of TCR signaling activation was not restricted to the reporter cell lines, as interaction with negatively charged surfaces also triggered TCR signaling in ex vivo Vγ1 γδ T cells. Taken together, these results explain long‐standing observations on the spontaneous reactivity of Vγ1Vδ6 TCR and demonstrate an unexpected antigen presentation‐independent mode of TCR activation by a spectrum of chemically unrelated polyanionic ligands.

show abstract

The γδTCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness

Cited by 171 publications

References 59 publications

Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy?

Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy?

Human γδ TCR Repertoires in Health and Disease

Recognition of synthetic polyanionic ligands underlies “spontaneous” reactivity of Vγ1 γδTCRs

Contact Info

Product

Resources

About