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.

Abstract 166: Activation of T Cells by Dendritic Cells in Hypertension: A Potential Role of Isoketal-modified Proteins

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Annet Kirabo ◽  
Jing Wu ◽  
Wei Chen ◽  
Salim R Thabet ◽  
Alfiya T Bikineyeva ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Angiotensin Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptive Immune System ◽  
Superoxide Production ◽  
Acid Oxidation ◽  
Induced Hypertension ◽  
Modified Proteins

The adaptive immune system contributes to development of hypertension but the mechanisms or antigens involved are not known. Isoketals (IsoKs) are products of arachidonic acid oxidation that can cross-link lysine residues on proteins which in turn can be immunogenic. We sought to determine if IsoK-modified proteins serve as neoantigens presented by dendritic cells (DCs) to activate T cells in hypertension. Superoxide production by DCs was increased 5-fold by angiotensin II infusion compared to sham treated mice (334.0±49.7 versus 65.8±4.5 pmol/mg protein). This was NADPH-dependent as it did not occur in the gp91 phox-/- mice. This increase in superoxide was associated with accumulation of IsoKs in DCs and activation of DC IL-6 production (1411.0±1330.2 versus 576.2±512.8 pg/ml). Treatment with a potent IsoK scavenger, 2-hydroxybenzylamine, markedly attenuated angiotensin II-induced hypertension (131.4 ± 9.4 mmHg versus 160.1 ± 5.1 mmHg in control mice). Finally we employed an immunization assay involving priming by adoptive transfer of DCs from either sham or angiotensin II-treated mice to naïve recipients. T cells from these recipients were then cultured for 10 days with DCs from either sham or angiotensin II treated mice. DCs from angiotensin II treated mice, but not sham mice, caused a striking activation of CD8 + cells in this assay, as reflected by proliferation and polarization to Tc1 and Tc17 phenotypes. These studies show that angiotensin II-induced hypertension activates DCs, in large part by causing superoxide production and formation of IsoKs. We propose that IsoK-modified proteins can be presented as neoantigens by DCs, which in turn trigger T cell activation leading to hypertension.

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

scholarly journals GAMMA-DELTA T CELLS MEDIATE ALPHA-BETA T CELL ACTIVATION IN ANGIOTENSIN II-INDUCED HYPERTENSION

2021 ◽  
Vol 39 (Supplement 1) ◽  
pp. e287
Author(s):  
Antoine Caillon ◽  
Pierre Paradis ◽  
Ernesto L. Schiffrin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Angiotensin Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Gamma Delta T Cells ◽  
Gamma Delta ◽  
Induced Hypertension ◽  
Alpha Beta

Abstract 043: Dendritic Cells Mediate Renal T Cell Activation in Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Nathan P Rudemiller ◽  
Jiandong Zhang ◽  
Gianna E Hammer ◽  
Yen-Rei A Yu ◽  
Robert Griffiths ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Effector T Cells ◽  
T Cell Subsets ◽  
Ang Ii ◽  
Blood Pressure Elevation

Activated T lymphocytes exacerbate hypertension in part by infiltrating the kidney to promote sodium retention. Dendritic cells (DCs) are the most potent antigen presenting cells that activate T cells and have been shown to contribute to hypertension. The current studies therefore explored whether DC-mediated activation of renal T cells can exaggerate the chronic hypertensive response to angiotensin (Ang) II. First, we confirmed that renal T cells undergo DC-mediated activation during the initiation of hypertension by analyzing immune cell populations in renal tissue via flow cytometry. In Fms-like tyrosine kinase 3 ligand-deficient (FLT3L KO) mice that lack DCs, the proportions of effector (CD44 hi CD62 lo ) T cells in the kidney were similar to wild-type (WT) controls at baseline (50±3 vs. 52±7% of CD3 + cells). However, after 5 days of Ang II-induced hypertension, the proportions of effector T cells were dramatically higher in the WT kidney versus the FLT3L KOs (69±3 vs. 52±3% of CD3 + cells; p<0.01), indicating that DCs activate T cells in hypertension. As DCs activate T cells in local lymph nodes, we phenotyped T cell subsets in the kidney lymph node (KLN) following 4 weeks of hypertension and detected elevated proportions of effector CD4 + T cells compared to baseline (10.7±2.0 vs. 6.9±0.8% of CD4 + T cells). The ubiquitin-editing protein A20 in DCs suppresses their capacity to stimulate T cells. Thus, mice with heterozygous deletion of A20 in DCs (CD11c-cre A20 flox/wt = DC ACT) harbor spontaneously active DCs that enhance T cell activation. To test the contribution of DC-mediated T cell activation to hypertension, we measured blood pressures in WT and DC ACT mice during 4 weeks of chronic Ang II infusion (300ng/kg/min). While MAPs were similar in the 2 groups at baseline, the DC ACT mice had an exaggerated chronic hypertensive response (143±2 vs. 131±4 mmHg; p=0.04) with more severe cardiac hypertrophy (7.3±0.3 vs. 6.4±0.4 mg/gm body wt; p<0.04). The KLNs from the DC ACT animals also contained higher proportions of effector T cells than controls (12.1±0.2 vs. 8.2±0.5% of CD3 + cells; p<0.01). In conclusion, DC-mediated activation of T cells promotes blood pressure elevation by facilitating the accumulation of effector T cells in the kidney during hypertension.

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).

scholarly journals Immunomodulatory Effects of Polysaccharide from Marine FungusPhoma herbarumYS4108 on T Cells and Dendritic Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Song Chen ◽  
Ran Ding ◽  
Yan Zhou ◽  
Xian Zhang ◽  
Rui Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Interleukin 12 ◽  
Related Factors ◽  
Knock Out ◽  
Specific Immunity

YCP, as a kind of natural polysaccharides from the mycelium of marine filamentous fungusPhoma herbarumYS4108, has great antitumor potentialviaenhancement of host immune response, but little is known about the molecular mechanisms. In the present study, we mainly focused on the effects and mechanisms of YCP on the specific immunity mediated by dendritic cells (DCs) and T cells. T cell /DC activation-related factors including interferon- (IFN-)γ, interleukin-12 (IL-12), and IL-4 were examined with ELISA. Receptor knock-out mice and fluorescence-activated cell sorting are used to analyze the YCP-binding receptor of T cells and DCs. RT-PCR is utilized to measure MAGE-A3 for analyzing the tumor-specific killing effect. In our study, we demonstrated YCP can provide the second signal for T cell activation, proliferation, and IFN-γproduction through binding to toll-like receptor- (TLR-) 2 and TLR-4. YCP could effectively promote IL-12 secretion and expression of markers (CD80, CD86, and MHC II)viaTLR-4 on DCs. Antigen-specific immunity against mouse melanoma cells was strengthened through the activation of T cells and the enhancement of capacity of DCs by YCP. The data supported that YCP can exhibit specific immunomodulatory capacity mediated by T cells and DCs.

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.

Regulation of Tim-3 function by binding to phosphatidylserine

2021 ◽  
Vol 478 (22) ◽  
pp. 3999-4004
Author(s):  
Lawrence P. Kane
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Transmembrane Protein ◽  
Cytotoxic T Cells ◽  
Cross Presentation ◽  
First Time

Tim-3 is a transmembrane protein that is highly expressed on subsets of chronically stimulated CD4+ helper and CD8+ cytotoxic T cells, with more transient expression during acute activation and infection. Tim-3 is also constitutively expressed by multiple types of myeloid cells. Like other TIM family members, Tim-3 can bind to phosphatidylserine displayed by apoptotic cells, and this interaction has been shown to mediate uptake of such cells by dendritic cells and cross-presentation of antigens to CD8+ T cells. In contrast, how the recognition of PS by Tim-3 might regulate the function of Tim-3+ T cells is not known. In their recent paper, Lemmon and colleagues demonstrate for the first time that recognition of PS by Tim-3 leads to enhanced T cell activation.

TREM-1 modulates dendritic cell maturation and dendritic cell–mediated T cell activation induced by ox-LDL

2020 ◽  
Author(s):  
Yunkai Wang ◽  
Jie Wang ◽  
Lu Han ◽  
Yun Li Shen ◽  
Jie Yun You ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Peripheral Blood ◽  
Dendritic Cell Maturation ◽  
Cell Maturation ◽  
Blood Monocytes

Abstract Background: Triggering receptor expressed on myeloid cells (TREM)-1is identified as a major upstream proatherogenic receptor. However, the cellular processes modulated by TREM-1 in the development of atherosclerosis and plaque destabilization has not been fully elucidated. In this study, we investigated the effects of TREM-1 on dendritic cell maturation and dendritic cell–mediated T-cell activation induced by oxidized low-density lipoprotein (ox-LDL) in atherogenesis. Methods: Human peripheral blood monocytes were differentiated to dendritic cells and stimulated by ox-LDL. Naive autologous T cells were co-cultured with pretreated dendritic cells.The expressionof TREM-1 and the production of inflammatory cytokines were assessed by real-time PCR, western blot and ELISA.The expression of immune factors was determined with FACS to evaluate dendritic cell maturation and T-cell activation. Results: Stimulation with ox-LDL promoted dendritic cell maturation, TREM-1 expression and T-cell activation, and exposure of T cells to ox-LDL-treated dendritic cells induced production of interferon-γ and IL-17. Blocking TREM-1 suppressed dendritic cell maturation with low expression of CD1a, CD40, CD86 and HLA-DR, decreased production of TNF-α, IL-1β, IL-6 and MCP-1, and increased secretion of TGF-β and IL-10. In addition, stimulation of ox-LDL induced miR-155, miR-27, Let-7c and miR-185 expression, whereas inhibition of TREM-1 repressed miRNA-155. Silencing TREM-1 or miRNA-155 increased SOCS1 expression induced by ox-LDL. T cells derived from carotid atherosclerotic plaques or healthy individuals showed similar result patterns. Conclusion: These data suggest that TREM-1 modulates maturation of dendritic cells and activation of plaque T cells induced by ox-LDL, a pivotal player in atherogenesis.

scholarly journals Contact-dependent delivery of IL-2 by dendritic cells to CD4 T cells in the contraction phase promotes their long-term survival

2019 ◽  
Vol 11 (2) ◽  
pp. 108-123
Author(s):  
Dan Tong ◽  
Li Zhang ◽  
Fei Ning ◽  
Ying Xu ◽  
Xiaoyu Hu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Immune Memory ◽  
Term Survival

Abstract Common γ chain cytokines are important for immune memory formation. Among them, the role of IL-2 remains to be fully explored. It has been suggested that this cytokine is critically needed in the late phase of primary CD4 T cell activation. Lack of IL-2 at this stage sets for a diminished recall response in subsequent challenges. However, as IL-2 peak production is over at this point, the source and the exact mechanism that promotes its production remain elusive. We report here that resting, previously antigen-stimulated CD4 T cells maintain a minimalist response to dendritic cells after their peak activation in vitro. This subtle activation event may be induced by DCs without overt presence of antigen and appears to be stronger if IL-2 comes from the same dendritic cells. This encounter reactivates a miniature IL-2 production and leads a gene expression profile change in these previously activated CD4 T cells. The CD4 T cells so experienced show enhanced reactivation intensity upon secondary challenges later on. Although mostly relying on in vitro evidence, our work may implicate a subtle programing for CD4 T cell survival after primary activation in vivo.

Sign in / Sign up

Export Citation Format

Share Document