Abstract 023: γδ T Cells Mediate αβ T Cell Activation in Angiotensin II-Induced Hypertension

Hypertension ◽  
2019 ◽  
Vol 74 (Suppl_1) ◽  
Author(s):  
Antoine Caillon ◽  
Pierre Paradis ◽  
Ernesto L Schiffrin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Angiotensin Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Γδ T Cells ◽  
Induced Hypertension

Abstract P347: γδ T Cells Drive CD4 + And CD8 + T Cell Activation In Hypertension

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Antoine Caillon ◽  
Pierre Paradis ◽  
Ernesto L Schiffrin
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Vascular Injury ◽  
T Cell Activation ◽  
Cell Activation ◽  
Γδ T Cells ◽  
Ang Ii ◽  
Adaptive Immune Cells ◽  
Induced Hypertension

Objective: Both innate (monocyte/macrophages) and adaptive immune cells (T lymphocytes) have been shown to play a role in the development of vascular injury in hypertension. Recently, we demonstrated that a small subset of “innate-like” T lymphocytes, expressing the γ/δ T cell receptor (TCR) rather than the αβ TCR, plays a key role in hypertension and vascular injury. We demonstrated an increased number and activation (CD69 + ) of γδ T cells during the development of hypertension caused by angiotensin (Ang) II infusion, and that deficiency in γδ T cells prevented Ang II-induced hypertension, resistance artery endothelial dysfunction and spleen T-cell activation in mice. We hypothesized that γδ T cells mediate activation of other T cells in hypertension. Method and Results: Fourteen to 15-week old male C57BL/6 wild-type (WT) mice were infused with Ang II (490 ng/kg/min, SC) for 3, 7 and 14 days (n=5-7) and spleen T cell profile was determined by flow cytometry. A correlation was demonstrated between the frequency (FREQ) and the number (#) of activated CD69 + γδ T cells and CD4 + CD69 + T cells (FREQ: r=0.41, P <0.05 and #: r=0.58, P <0.001) and CD8 + CD69 + T cells (FREQ: r=0.36, P <0.05 and #: r=0.50, P <0.01). We also demonstrated a high correlation between the # of CD69 + γδ T cells expressing CD27, a marker of interferon-γ expressing cells and a member of the T-T interaction molecules, with CD4 + CD69 + (r=0.88, P <0.001) and CD8 + CD69 + (r=0.81, P <0.01) T cells after 7 days of Ang II infusion. Conclusion: This study demonstrated an association between CD27 + CD69 + γδ T cells and activated T cells. These results suggest that γδ T cells drive activation of other T cells in Ang II-induced hypertension. Targeting γδ T cells may contribute to reduce inflammation in hypertension.

Abstract 242: Superoxide and Isoketal Neo-antigen formation in Dendritic Cells from Hypertensive mice activate T cells and promote Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Annet Kirabo ◽  
Jing Wu ◽  
Salim R Thabet ◽  
Alfiya T Bikineyeva ◽  
Sergey Dikalov ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Angiotensin Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Superoxide Production ◽  
Blood Pressure Elevation ◽  
Induced Hypertension ◽  
Endogenous Proteins

Superoxide and inflammation contribute to the genesis of hypertension but the mechanisms involved are not fully understood. We examined the hypothesis that oxidative stress in dendritic cells (DCs) alters endogenous proteins via Isoketal-modification leading to formation of neo-antigens, T cell activation and blood pressure elevation. DCs isolated from mice with angiotensin II-induced hypertension had a significant increase in NADPH oxidase-dependent superoxide production when compared to sham-treated mice (334.0±49.7 versus 65.8±4.5 pmol/mg protein). This was associated with an exuberant DC accumulation of protein-isoketal adducts and activation of IL-6, IL-1β and IL-23 production. DCs from hypertensive mice but not sham mice promoted survival and proliferation of CD8 + T cells in culture. Scavenging of isoketals not only prevented activation and immunogenicity of DCs, but also markedly attenuated angiotensin II-induced hypertension (142.59 ± 8.98 mmHg versus 175.53 ± 5.19 mmHg in controls). Moreover, adaptive transfer of DCs from hypertensive mice primed development of hypertension in mice given a sub-pressor dose of angiotensin II (157.45 ± 33.86 mmHg versus 119.90 ± 17.33 mmHg in controls). These studies show that angiotensin II-induced hypertension activates DCs, in large part by causing superoxide production and formation of isoketals. We propose that Isoketal-modified proteins can be presented as neo-antigens by DCs, which in turn trigger T cell activation leading to hypertension.

scholarly journals γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation

Cell ◽  
2020 ◽  
Vol 183 (4) ◽  
pp. 1134-1136
Author(s):  
Donnele Daley ◽  
Constantinos Pantelis Zambirinis ◽  
Lena Seifert ◽  
Neha Akkad ◽  
Navyatha Mohan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Γδ T Cells

scholarly journals γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation

Cell ◽  
2016 ◽  
Vol 166 (6) ◽  
pp. 1485-1499.e15 ◽  
Author(s):  
Donnele Daley ◽  
Constantinos Pantelis Zambirinis ◽  
Lena Seifert ◽  
Neha Akkad ◽  
Navyatha Mohan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Γδ T Cells

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.

Abstract MP05: The Mechanism Of The Pvat Pro-inflammatory Micro-environment Formation During The Development Of High Fat Diet-induced Hypertension

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Yining Jin ◽  
Omar Kana ◽  
Ramya Kumar ◽  
Rance Nault ◽  
Hannah Garver ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
High Fat Diet ◽  
Cell Activation ◽  
Control Diet ◽  
Rna Seq ◽  
High Fat ◽  
Induced Hypertension ◽  
Th17 Differentiation

There is considerable evidence for a causative role for T cells in hypertension, including studies with immunosuppressive drugs and T cell-deficient models. Our previous studies showed that soluble mediators from mesenteric perivascular adipose tissue (mPVAT) modulate T cell function. Specifically, conditioned media from mPVAT (mPVAT-CM) from Dahl S rats on a high fat diet (HFD) promoted expression of the pro-inflammatory cytokines, IFNg, IL-17a and GM-CSF, by activated T cells. Furthermore, the Dahl S rats on HFD will later develop hypertension. Hypothesis: mPVAT is stimulated to produce immunomodulatory mediators that promotes Th1/17 differentiation preceding the development of HFD-induced hypertension. We conducted bulk RNA-seq on activated splenocytes cultured in mPVAT-CM from Dahl S rats on either control or HFD for 10 weeks. In accordance with our previous studies, PVAT-CM from HFD-fed rats significantly upregulated many genes associated with IFNg/IL-17 induction, including Mpeg1, Lyz2 and Tnfsf4 (5.0±1.78, 3.70±0.53 and 1.78±0.42 fold over Control diet, respectively). In contrast, Th2/Treg-associated genes, such as Ctla2a (-0.27±0.02) and Ccr4 (-0.41±0.03) were downregulated. We also performed single cell (sc) RNA-seq on the PVAT stromal vascular fraction (SVF) and found that acute inflammatory genes were enriched in the HFD group. Together with the bulk RNA-seq on mPVAT, these data strongly suggest that the pro-inflammatory mPVAT micro-environment may promote Th1/Th17 differentiation. To identify mediators in PVAT-CM that may induce Th1/Th17 differentiation, we compared the bulk RNA-seq on splenocytes cultured in PVAT-CM with bulk RNA-seq conducted on the whole mPVAT itself. We found that a T cell co-stimulatory receptor DPP4 (CD26), which is closely associated with T cell activation was significantly increased in mPVAT from HFD-fed rats (33.4±2.3 HFD vs. 15.3±1.8 Control diet). We also observed an increase in DPP4 global expression from mPVAT SVF in HFD-fed rats, as determined by scRNA-seq. Conclusion: The data suggest that HFD promotes the IFNg and IL-17a pathways in PVAT, which precedes hypertension in Dahl S rats and correlates with an increase in expression of DPP-4, a gene that promotes T cell activation. (NIH P01 HL070687).

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 Integrated immune networks in SARS-CoV-2 infected pregnant women reveal differential NK cell and unconventional T cell activation

2021 ◽  
Author(s):  
Jennifer R Habel ◽  
Brendon Y Chua ◽  
Lukasz Kedzierski ◽  
Kevin J Selva ◽  
Timon Damelang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Pregnant Women ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Γδ T Cells ◽  
Immunological Parameters ◽  
Immunological Responses ◽  
Mait Cells

ABSTRACTAlthough pregnancy poses a greater risk for severe COVID-19, the underlying immunological changes associated with SARS-CoV-2 infection during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in pregnant and non-pregnant women during acute and convalescent COVID-19 up to 258 days post symptom onset, quantifying 217 immunological parameters. Additionally, matched maternal and cord blood were collected from COVID-19 convalescent pregnancies. Although serological responses to SARS-CoV-2 were similar in pregnant and non-pregnant women, cellular immune analyses revealed marked differences in key NK cell and unconventional T cell responses during COVID-19 in pregnant women. While NK cells, γδ T cells and MAIT cells displayed pre-activated phenotypes in healthy pregnant women when compared to non-pregnant age-matched women, activation profiles of these pre-activated NK and unconventional T cells remained unchanged at acute and convalescent COVID-19 in pregnancy. Conversely, activation dynamics of NK and unconventional T cells were prototypical in non-pregnant women in COVID-19. In contrast, activation of αβ CD4+ and CD8+ T cells, T follicular helper cells and antibody-secreting cells was similar in pregnant and non-pregnant women with COVID-19. Elevated levels of IL-1β, IFN-γ, IL-8, IL-18 and IL-33 were also found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, our study provides the first comprehensive map of longitudinal immunological responses to SARS-CoV-2 infection in pregnant women, providing insights into patient management and education during COVID-19 pregnancy.

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