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.

Kinetics of intratumoral T-cell activation during chemoradiation for cervical cancer.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 6-6
Author(s):  
Stephanie Dorta-Estremera ◽  
Krishna Nookala Sita Mahalakshmi ◽  
Ananta V Yanamandra ◽  
Lauren Elizabeth Colbert ◽  
Guojun Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Radiation Therapy ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Immune Cell ◽  
Matched Pair ◽  
Kinetics Of

6 Background: Limited data in cancer patients have suggested that chemotherapy and radiation impact local and systemic immune cell populations. Radiation therapy (RT) is known to deplete circulating lymphocytes but is thought to increase local antigen presentation. The dynamics of these competing effects on the kinetics of intratumoral infiltration and expansion of activated and immunoregulatory T cells are unknown. Methods: We prospectively evaluated intratumoral immune infiltration during fractionated RT using multi-spectral flow cytometry. Cervical brushings were obtained from 14 patients before (baseline) and during RT (week 1, 3 and 5). Cells collected from the cervical brushings were stained with a 16-color panel of antibodies that included markers to identify T cell and dendritic cell subsets with activation and suppressor molecules. Changes in immune cell subsets at different time points were evaluated and calculated using matched-pair analysis with Wilcoxon rank sum test. Results: CD3+ T cells declined over the first week of treatment (28% of CD3 at baseline, vs. 14.8% at week 1, p = 0.0273). The percentage of CD3+ cells subsequently increased at 3 weeks (25.6%) and 5 weeks (37.8%). Both CD8+ and CD4+ T cells underwent a decline at week 1 followed by expansion at week 3 and 5. Percentages of regulatory T cells (CD4+Foxp3+) showed a similar trend of reduction and further expansion but did not reach significance. The percentage of CD8+ T cells expressing the T cell activation marker CD69 and the cytotoxic protease Granzyme B (GrzB) continuously increased over time (CD69+: 11.8%, 27.7%, 38.7%, 57.5%, and GrzB+: 23.9%, 53.2%, 48.1%, 58.2%). While the percentage of dendritic cells (CD11c+ CD11b+) was stable during treatment, the subset of activated dendritic cells expressing CD86 increased at week 1 and subsequently declined (week 1, 19.1% vs week 5, 9.8%, p = 0.0642). Conclusions: Activated CD8+ effector T cells expand in the cervix during radiation therapy. Moreover, in the first week of treatment, CD8+ T cells contract while dendritic cells undergo activation suggesting this may be a critical time to intervene to maximize anti-tumor immunity.

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 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.

EP.WE.805From bench to bedside; A rationale for Immunotherapy in the adjuvant setting for Oesophageal cancer

2021 ◽  
Vol 108 (Supplement_7) ◽  
Author(s):  
Noel Donlon ◽  
Maria Davern ◽  
Andrew Sheppard ◽  
John Reynolds ◽  
Joanne Lysaght
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Single Agent ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Post Surgery ◽  
Post Operative Period

Abstract Background Immunotherapy is being intensively investigated for its utilisation in the curative setting as a single agent and in the multimodal setting, however, the most appropriate time to incorporate ICIs remains unknown. Our study profiles systemic anti-tumour immunity perioperatively to provide a rationale for adjuvant immunotherapy. Methods Systemic immunity was immunophenotyped pre and post-oesophagectomy on days 0, 1, 3, 7 and week 6 by flow cytometry (n = 14). The frequency of circulating lymphocytes, T cells, cytotoxic and helper T lymphocytes was profiled longitudinally including the proportion of T cell subsets in circulation. This study also profiled immune checkpoint expression on circulating T cells including: PD-1, CTLA-4, TIGIT, TIM-3, LAG-3, PD-L1 and PD-L2. Markers of immunogenicity (calreticulin, HMGB1 and MIC-A/B) were also assessed. Results The frequency of circulating CD27 + T cells increases sequentially in the immediate post-operative period peaking on day 7 in OAC patients. (p &lt; 0.01) There is a sequential decrease in the percentage of effector memory and central memory T cells in circulation and an increase in the percentage of naïve T cells in peripheral circulation of OAC patients in the immediate post-operative period. The expression of CTLA-4 on the surface of circulating CD4 + T cells decreases 6 weeks post-operatively in OAC patients. Conclusions We observed increased T cell activation and immune checkpoints immediately post-surgery with returns to baseline by week 6. These results suggest that immune checkpoint inhibitors such as anti-PD-1 may be beneficial immediately post-surgery to maintain T cell activation and prevent exhaustion of this increased population of activated T cells observed immediately post-surgery.

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.

scholarly journals A novel form of immune signaling revealed by transmission of the inflammatory mediator serotonin between dendritic cells and T cells

Blood ◽  
2006 ◽  
Vol 107 (3) ◽  
pp. 1010-1017 ◽  
Author(s):  
Peta J. O'Connell ◽  
Xiangbin Wang ◽  
Matilde Leon-Ponte ◽  
Corrie Griffiths ◽  
Sandeep C. Pingle ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Activated T Cells ◽  
Immune Synapse ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
5 Ht Uptake

AbstractAdaptive immunity is triggered at the immune synapse, where peptide-major histocompatibility complexes and costimulatory molecules expressed by dendritic cells (DCs) are physically presented to T cells. Here we describe transmission of the inflammatory monoamine serotonin (5-hydroxytryptamine [5-HT]) between these cells. DCs take up 5-HT from the microenvironment and from activated T cells (that synthesize 5-HT) and this uptake is inhibited by the antidepressant, fluoxetine. Expression of 5-HT transporters (SERTs) is regulated by DC maturation, exposure to microbial stimuli, and physical interactions with T cells. Significantly, 5-HT sequestered by DCs is stored within LAMP-1+ vesicles and subsequently released via Ca2+-dependent exocytosis, which was confirmed by amperometric recordings. In turn, extracellular 5-HT can reduce T-cell levels of cAMP, a modulator of T-cell activation. Thus, through the uptake of 5-HT at sites of inflammation, and from activated T cells, DCs may shuttle 5-HT to naive T cells and thereby modulate T-cell proliferation and differentiation. These data constitute the first direct measurement of triggered exocytosis by DCs and reveal a new and rapid type of signaling that may be optimized by the intimate synaptic environment between DCs and T cells. Moreover, these results highlight an important role for 5-HT signaling in immune function and the potential consequences of commonly used drugs that target 5-HT uptake and release.

scholarly journals Tim-3 co-stimulation promotes short-lived effector T cells, restricts memory precursors, and is dispensable for T cell exhaustion

2018 ◽  
Vol 115 (10) ◽  
pp. 2455-2460 ◽  
Author(s):  
Lyndsay Avery ◽  
Jessica Filderman ◽  
Andrea L. Szymczak-Workman ◽  
Lawrence P. Kane
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Chronic Infection ◽  
Cell Activation ◽  
Effector T Cells ◽  
Mtor Signaling ◽  
T Cell Exhaustion ◽  
Inhibitory Protein ◽  
Cell Exhaustion

Tim-3 is highly expressed on a subset of T cells during T cell exhaustion in settings of chronic viral infection and tumors. Using lymphocytic choriomeningitis virus (LCMV) Clone 13, a model for chronic infection, we found that Tim-3 was neither necessary nor sufficient for the development of T cell exhaustion. Nonetheless, expression of Tim-3 was sufficient to drive resistance to PD-L1 blockade therapy during chronic infection. Strikingly, expression of Tim-3 promoted the development of short-lived effector T cells, at the expense of memory precursor development, after acute LCMV infection. These effects were accompanied by increased Akt/mTOR signaling in T cells expressing endogenous or ectopic Tim-3. Conversely, Akt/mTOR signaling was reduced in effector T cells from Tim-3–deficient mice. Thus, Tim-3 is essential for optimal effector T cell responses, and may also contribute to exhaustion by restricting the development of long-lived memory T cells. Taken together, our results suggest that Tim-3 is actually more similar to costimulatory receptors that are up-regulated after T cell activation than to a dominant inhibitory protein like PD-1. These findings have significant implications for the development of anti–Tim-3 antibodies as therapeutic agents.

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