Abstract 2262: Chemotherapy, checkpoint inhibition, and MGMT-modified adoptive gamma-delta (γδ) T cell-based therapy to treat post-resection, primary glioblastomas

2019 ◽  
Author(s):  
Sailesh Pillai ◽  
George Y. Gillespie ◽  
Louis B. Nabors ◽  
Samantha Langford ◽  
Catherine P. Langford ◽  
...  
Keyword(s):  
T Cell ◽  
Checkpoint Inhibition ◽  
Γδ T Cell ◽  
Gamma Delta ◽  
Cell Based Therapy ◽  
Primary Glioblastomas

scholarly journals Differential Activation of V γ4V δ1 and V γ9V δ2 Cord Blood Derived Gamma Delta T Cells upon Exposure to EBV-Lcl and K562 Cells

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2790-2790
Author(s):  
Jeremy Wee Kiat Ng ◽  
Joey Lai ◽  
Tony Kiat Hon Lim ◽  
William YK Hwang ◽  
Shang Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Single Cell ◽  
Γδ T Cells ◽  
Rapid Expansion ◽  
Leukemia Cell Line ◽  
Γδ T Cell ◽  
Gamma Delta

Abstract Gamma-delta (γδ) T cells have emerged as a promising candidate for adoptive cellular immunotherapy. To harness and maximize the anti-leukemia properties of these cells, we sort to comprehensively profile the transcriptomic signatures and immune repertoire of in vitro expanded γδ T cell products. Given the reported diverse TCR γδ repertoire and naïve nature of γδ T cells found in human cord blood (CB γδ), we serially track the molecular and cellular changes in these cells upon activation in expansion cultures. Based on the established viral reactivities of γδ T cell as well as prior studies showing their cross reactivities against leukemia and cancer cells, we had previously shown that stimulating CB γδ with an irradiated EBV-LCL feeder cell-based rapid expansion protocol (REP) is capable of generating cell products with potent and specific cytotoxicity against human AML cells. In the present study, using single cell RNA sequencing (scRNA-seq) coupled with single cell TCR γδ repertoire analysis, we compared the transcription signatures between our REP expanded γδ T cell (REP γδ) and non-manipulated γδ T cells reported in literatures, showing the progressive acquisition of an adult PB derived γδ T cell (PB γδ)-like cell states. Time course analysis demonstrated complex T cell activation and maturation trajectories correlating with variable level of clonal induction throughout the course of in vitro expansion. At the end of expansion, the harvested REP γδ are predominantly of the V γ4V δ1 subtype. Nevertheless, upon exposing REP γδ to target leukemia cell line K562, outgrowth of other non-V γ4V δ1 as well as the semi-invariant V γ9V δ2 cells were observed. Taken together, our data shows that as CB γδ expand and differentiate in culture, they adopt an adult PB γδ-like program. More importantly, our data highlights the rich clonal composition of in vitro expanded CB γδ, with different clonotypes being variably activated upon exposure to different stimuli. Such characteristics can potentially overcome the challenges of cancer heterogeneity and cell persistence, with the potential of improving outcomes in cell immunotherapy. Disclosures No relevant conflicts of interest to declare.

Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells

Science ◽  
2020 ◽  
Vol 367 (6478) ◽  
pp. eaay5516 ◽  
Author(s):  
Marc Rigau ◽  
Simone Ostrouska ◽  
Thomas S. Fulford ◽  
Darryl N. Johnson ◽  
Katherine Woods ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
T Cell Receptors ◽  
Protective Immunity ◽  
Cell Activation ◽  
Molecular Targets ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Gamma Delta

Gamma delta (γδ) T cells are essential to protective immunity. In humans, most γδ T cells express Vγ9Vδ2+ T cell receptors (TCRs) that respond to phosphoantigens (pAgs) produced by cellular pathogens and overexpressed by cancers. However, the molecular targets recognized by these γδTCRs are unknown. Here, we identify butyrophilin 2A1 (BTN2A1) as a key ligand that binds to the Vγ9+ TCR γ chain. BTN2A1 associates with another butyrophilin, BTN3A1, and these act together to initiate responses to pAg. Furthermore, binding of a second ligand, possibly BTN3A1, to a separate TCR domain incorporating Vδ2 is also required. This distinctive mode of Ag-dependent T cell activation advances our understanding of diseases involving pAg recognition and creates opportunities for the development of γδ T cell–based immunotherapies.

scholarly journals Association of γδ T Cells with Disease Severity and Mortality in Septic Patients

2013 ◽  
Vol 20 (5) ◽  
pp. 738-746 ◽  
Author(s):  
Juan C. Andreu-Ballester ◽  
Constantino Tormo-Calandín ◽  
Carlos Garcia-Ballesteros ◽  
J. Pérez-Griera ◽  
Victoria Amigó ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymphocyte Subsets ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Control Group ◽  
Gamma Delta T Cells ◽  
Γδ T Cell ◽  
Gamma Delta ◽  
First Line

ABSTRACTGamma-delta T cells are the most abundant of all epithelial-resident lymphocytes and are considered a first line of defense against pathogens in the mucosa. Our objective was to confirm the reduction in γδ T cell subsets and its relationship with mortality in patients with sepsis. We studied 135 patients with sepsis attended in the emergency department and intensive care unit of two hospitals and compared them with a similar control group of healthy subjects. The αβ and γδ T cell subsets were determined via flow cytometry according to the stage of the sepsis and its relationship with mortality. All the lymphocyte subsets were reduced with respect to the corresponding subsets in the control group. All the γδ T cell populations decreased significantly as the septic picture worsened. Furthermore, γδ T cells showed decreases at days 2, 3, and 4 from the start of sepsis. Twenty-six patients with sepsis died (19.3%). The γδ T cells, specifically, the CD3+CD56+γδ T cells, were significantly reduced in those septic patients who died. Our results indicate that, during sepsis, γδ T cells show the largest decrease and this reduction becomes more intense when the septic process becomes more severe. Mortality was associated with a significant decrease in γδ T cells.

scholarly journals Natural Self-Ligand Gamma Delta T Cell Receptors (γδTCRs) Insight: The Potential of Induced IgG

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 436 ◽  
Author(s):  
Thamires Rodrigues de Sousa ◽  
Jefferson Russo Victor
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
Cell Receptor ◽  
Actual State ◽  
Γδ T Cell ◽  
Gamma Delta ◽  
Cell Receptors ◽  
Theoretical Contribution ◽  
Almost All ◽  
Gamma Delta T Cell

A γδ T cell acquires functional properties in response to the gamma delta T cell receptor γδTCR signal strength during its development in the thymus. The elucidation of the potential ligands of γδ T cell receptors are of extreme importance; however, they are still not understood. Here we revise the actual state of the art of candidates to exert the function of γδTCR ligands, and propose a theoretical contribution about new potential ligands of γδTCRs, based on biological and hypothetical pieces of evidence in the literature. In conclusion, we hypothetically suggest a possible role of induced antibodies according to the individual’s immune status, mainly of the IgG subclass, acting as γδTCR ligands. Considering that IgG production is involved in some essential immunotherapy protocols, and almost all vaccination protocols, our discussion opens a new and broad field to further exploration.

Characterisation of gamma delta (γδ) T cell populations in patients with sepsis

2014 ◽  
Vol 39 (2) ◽  
pp. 210-216 ◽  
Author(s):  
Helen F. Galley ◽  
Damon A. Lowes ◽  
Keith Thompson ◽  
Naomi D. Wilson ◽  
Carol A. Wallace ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Populations ◽  
Γδ T Cell ◽  
Gamma Delta

scholarly journals Gamma Delta TCR and the WC1 Co-Receptor Interactions in Response to Leptospira Using Imaging Flow Cytometry and STORM

2021 ◽  
Vol 12 ◽  
Author(s):  
Alexandria Gillespie ◽  
Maria Gracia Gervasi ◽  
Thillainayagam Sathiyaseelan ◽  
Timothy Connelley ◽  
Janice C. Telfer ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Temporal Dynamics ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Gamma Delta ◽  
Cellular Activation ◽  
Imaging Flow Cytometry

The WC1 cell surface family of molecules function as hybrid gamma delta (γδ) TCR co-receptors, augmenting cellular responses when cross-linked with the TCR, and as pattern recognition receptors, binding pathogens. It is known that following activation, key tyrosines are phosphorylated in the intracytoplasmic domains of WC1 molecules and that the cells fail to respond when WC1 is knocked down or, as shown here, when physically separated from the TCR. Based on these results we hypothesized that the colocalization of WC1 and TCR will occur following cellular activation thereby allowing signaling to ensue. We evaluated the spatio-temporal dynamics of their interaction using imaging flow cytometry and stochastic optical reconstruction microscopy. We found that in quiescent γδ T cells both WC1 and TCR existed in separate and spatially stable protein domains (protein islands) but after activation using Leptospira, our model system, that they concatenated. The association between WC1 and TCR was close enough for fluorescence resonance energy transfer. Prior to concatenating with the WC1 co-receptor, γδ T cells had clustering of TCR-CD3 complexes and exclusion of CD45. γδ T cells may individually express more than one variant of the WC1 family of molecules and we found that individual WC1 variants are clustered in separate protein islands in quiescent cells. However, the islands containing different variants merged following cell activation and before merging with the TCR islands. While WC1 was previously shown to bind Leptospira in solution, here we showed that Leptospira bound WC1 proteins on the surface of γδ T cells and that this could be blocked by anti-WC1 antibodies. In conclusion, γδ TCR, WC1 and Leptospira interact directly on the γδ T cell surface, further supporting the role of WC1 in γδ T cell pathogen recognition and cellular activation.

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