Effector functions and control of human γδ T-cell activation

1999 ◽  
Vol 1 (3) ◽  
pp. 255-261 ◽  
Author(s):  
Dieter Kabelitz
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Γδ T Cell ◽  
Effector Functions ◽  
And Control

Hspa8 and ICAM‐1 as damage‐induced mediators of γδ T cell activation

2021 ◽  
Author(s):  
Margarete D. Johnson ◽  
Michel F. Otuki ◽  
Daniela A. Cabrini ◽  
Ross Rudolph ◽  
Deborah A. Witherden ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Γδ T Cell

107 Effects of IL-2 and IL-15 on the proliferative and antitumor capacities of allogeneic CD20 CAR-engineered γδ T cells in a 3D B cell lymphoma spheroid assay

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A119-A119
Author(s):  
Lu Bai ◽  
Kevin Nishimoto ◽  
Mustafa Turkoz ◽  
Marissa Herrman ◽  
Jason Romero ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytokine Production ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Car T

BackgroundAutologous chimeric antigen receptor (CAR) T cells have been shown to be efficacious for the treatment of B cell malignancies; however, widespread adoption and application of CAR T cell products still face a number of challenges. To overcome these challenges, Adicet Bio is developing an allogeneic γδ T cell-based CAR T cell platform, which capitalizes on the intrinsic abilities of Vδ1 γδ T cells to recognize and kill transformed cells in an MHC-unrestricted manner, to migrate to epithelial tissues, and to function in hypoxic conditions. To gain a better understanding of the requirements for optimal intratumoral CAR Vδ1 γδ T cell activation, proliferation, and differentiation, we developed a three-dimensional (3D) tumor spheroid assay, in which tumor cells acquire the structural organization of a solid tumor and establish a microenvironment that has oxygen and nutrient gradients. Moreover, through the addition of cytokines and/or tumor stromal cell types, the spheroid microenvironment can be modified to reflect hot or cold tumors. Here, we report on the use of a 3D CD20+ Raji lymphoma spheroid assay to evaluate the effects of IL-2 and IL-15, positive regulators of T cell homeostasis and differentiation, on the proliferative and antitumor capacities of CD20 CAR Vδ1 γδ T cells.MethodsMolecular, phenotypic, and functional profiling were performed to characterize the in vitro dynamics of the intraspheroid CD20 CAR Vδ1 γδ T cell response to target antigen in the presence of IL-2, IL-15, or no added cytokine.ResultsWhen compared to no added cytokine, the addition of IL-2 or IL-15 enhanced CD20 CAR Vδ1 γδ T cell activation, proliferation, survival, and cytokine production in a dose-dependent manner but were only able to alter the kinetics of Raji cell killing at low effector to target ratios. Notably, differential gene expression analysis using NanoString nCounter® Technology confirmed the positive effects of IL-2 or IL-15 on CAR-activated Vδ1 γδ T cells as evidenced by the upregulation of genes involved in activation, cell cycle, mitochondrial biogenesis, cytotoxicity, and cytokine production.ConclusionsTogether, these results not only show that the addition of IL-2 or IL-15 can potentiate CD20 CAR Vδ1 γδ T cell activation, proliferation, survival, and differentiation into antitumor effectors but also highlight the utility of the 3D spheroid assay as a high throughput in vitro method for assessing and predicting CAR Vδ1 γδ T cell activation, proliferation, survival, and differentiation in hot and cold tumors.

A comparative view on vitamin C effects on αβ‐ versus γδ T‐cell activation and differentiation

2020 ◽  
Vol 107 (6) ◽  
pp. 1009-1022 ◽  
Author(s):  
Christian Peters ◽  
Léonce Kouakanou ◽  
Dieter Kabelitz
Keyword(s):  
T Cell ◽  
Vitamin C ◽  
T Cell Activation ◽  
Cell Activation ◽  
Γδ T Cell

scholarly journals Mechanisms of Vδ1 γδ T Cell Activation by Microbial Components.

2004 ◽  
Vol 173 (3) ◽  
pp. 2199.3-2199
Author(s):  
Hiranmoy Das ◽  
Masahiko Sugita ◽  
Michael B. Brenner
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Γδ T Cell

CD277 takes the lead in human γδ T-cell activation

Blood ◽  
2012 ◽  
Vol 120 (11) ◽  
pp. 2159-2161 ◽  
Author(s):  
Dieter Kabelitz
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Γδ T Cell

scholarly journals Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset

Blood ◽  
2012 ◽  
Vol 120 (11) ◽  
pp. 2269-2279 ◽  
Author(s):  
Christelle Harly ◽  
Yves Guillaume ◽  
Steven Nedellec ◽  
Cassie-Marie Peigné ◽  
Hannu Mönkkönen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Subset ◽  
Cell Receptor ◽  
Causal Link ◽  
Target Cells ◽  
Γδ T Cell ◽  
Vγ9vδ2 T Cells

Abstract Human peripheral Vγ9Vδ2 T cells are activated by phosphorylated metabolites (phosphoagonists [PAg]) of the mammalian mevalonate or the microbial desoxyxylulose-phosphate pathways accumulated by infected or metabolically distressed cells. The underlying mechanisms are unknown. We show that treatment of nonsusceptible target cells with antibody 20.1 against CD277, a member of the extended B7 superfamily related to butyrophilin, mimics PAg-induced Vγ9Vδ2 T-cell activation and that the Vγ9Vδ2 T-cell receptor is implicated in this effect. Vγ9Vδ2 T-cell activation can be abrogated by exposing susceptible cells (tumor and mycobacteria-infected cells, or aminobisphosphonate-treated cells with up-regulated PAg levels) to antibody 103.2 against CD277. CD277 knockdown and domain-shuffling approaches confirm the key implication of the CD277 isoform BTN3A1 in PAg sensing by Vγ9Vδ2 T cells. Fluorescence recovery after photobleaching (FRAP) experiments support a causal link between intracellular PAg accumulation, decreased BTN3A1 membrane mobility, and ensuing Vγ9Vδ2 T-cell activation. This study demonstrates a novel role played by B7-like molecules in human γδ T-cell antigenic activation and paves the way for new strategies to improve the efficiency of immunotherapies using Vγ9Vδ2 T cells.

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.

Immunologic Effects of CCR5 Blockade in Graft-Versus-Host Disease Prophylaxis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 920-920 ◽  
Author(s):  
Ryan H Moy ◽  
Austin P Huffman ◽  
Lee P Richman ◽  
Lisa Crisalli ◽  
James A Hoxie ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Graft Versus Host Disease ◽  
Cell Activation ◽  
Ccr5 Expression ◽  
Allogeneic Hsct ◽  
Graft Versus Host ◽  
And Control ◽  
Ccr5 Blockade

Abstract Background: Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Experimental models and clinical studies suggest that blocking lymphocyte trafficking with the chemokine receptor CCR5 antagonist maraviroc (MVC) ameliorates visceral GVHD. However, the effects of CCR5 blockade on immune reconstitution and activation in allogeneic HSCT recipients remain unknown. Methods: We previously reported a phase I/II study of 38 high-risk patients undergoing reduced-intensity allogeneic HSCT with standard GVHD prophylaxis (tacrolimus, methotrexate) combined with brief (33-day) MVC treatment. We compared the clinical and immunologic outcomes of these patients to a contemporary control cohort of 115 consecutive patients undergoing allogeneic HSCT with standard GVHD prophylaxis alone. Multivariate analysis was used to assess the effect of MVC treatment on the incidence of GVHD. Flow cytometry on day 30 and day 60 PBMC samples was used to monitor immune cell subsets, T cell activation markers and chemokine receptor expression. We also used a multiplex Luminex assay to quantify serum cytokine levels at day 30. Results: Since our initial report, longer follow up (median 37 months) now shows that patients who received MVC have reduced incidence rates of acute grade II-IV GVHD (adjusted hazard ratio [aHR]=0.42, 95% CI 0.21-0.84, p=0.015) and grade III-IV GVHD (aHR=0.43, 95% CI 0.17-1.09, p=0.075) compared to our control cohort (Figure 1). There was no difference in chronic GVHD between the groups. Early lymphocyte recovery was similar between MVC and control cohorts, with no significant difference in absolute lymphocyte, CD4 T cell and CD8 T cell counts at day 30. We observed increased CCR5 expression on CD4 T cells, CD8 T cells and B cells at day 30 in response to MVC treatment (Figure 2A-B). However, CCR5 expression on these cell types equalized between MVC and control patients by day 60. Day 30 MVC samples also demonstrated decreased percentages of CD38+ CD4 T cells and HLA-DR+ CD8 T cells (Figure 2C-D), an effect that also faded by day 60. These data suggest that inhibition of lymphocyte trafficking with CCR5 blockade dampens peripheral T cell activation. Notably, some patients developed acute GVHD despite MVC prophylaxis, and therefore we investigated differences between MVC responders and non-responders. Patients who developed GVHD had a higher percentage of activated CD38+ CD4 T cells in peripheral blood (Figure 3A) and an increased proportion of naive CD4 (36.5% vs 18.1% p=0.005) and CD8 (35.5% vs 11.9% p=0.0008) T cells, which has been associated with the development of GVHD. We also observed higher CCR5 expression on CD8 T cells from MVC non-responders (CCR5 MFI 8800 vs 6595, p=0.02). Intriguingly, while MVC responders and non-responders had similar serum concentrations of CCR5 ligands (MIP-1a, MIP-1b, Rantes), MVC non-responders had elevated levels of CXCR3 ligands (IP-10, MIG) (Figure 3B-C). Taken together, these data suggest that lymphocyte migration via CXCR3 may be a potential escape mechanism for GVHD initiation and T cell activation in the setting of CCR5 blockade. Conclusion: Brief CCR5 blockade in high-risk patients inhibits T cell activation and reduces the incidence of GVHD. MVC does not inhibit early lymphocyte recovery, which was similar in treated and control patients. This supports the hypothesis that MVC treatment would not impair graft-versus-leukemia activity. Our analysis of immunologic outcomes of MVC reveals a distinct immunologic effect for CCR5 blockade in allogeneic HSCT recipients and suggests a novel resistance mechanism. These studies bolster CCR5 antagonism as an effective strategy for GVHD prevention and provide support for extended MVC treatment duration and investigation into CXCR3 as a therapeutic target. Figure 1. Incidence of GVHD in control and MVC cohorts Figure 1. Incidence of GVHD in control and MVC cohorts Figure 2. MVC increases CCR5 expression and dampens T cell activation at day 30 *p<0.05; **p<0.01; ***p<0.001 Figure 2. MVC increases CCR5 expression and dampens T cell activation at day 30 *p<0.05; **p<0.01; ***p<0.001 Figure 3. Increased T cell activation and serum CXCR3 ligands in MVC non-responders *p<0.05; ***p<0.001 Figure 3. Increased T cell activation and serum CXCR3 ligands in MVC non-responders *p<0.05; ***p<0.001 Disclosures Off Label Use: Off label use of CCR5 antagonist maraviroc for the prevention of graft-versus-host disease. Vonderheide:Pfizer: Research Funding. Porter:Pfizer: Research Funding.

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