Abstract 1533: CD4+ T cells reprogram tumor metabolism and drive oxidative stress-induced tumor destruction

The mitochondrial antiviral signaling protein (MAVS) is part of the cell’s innate immune mechanism of defense. MAVS mRNA is bicistronic and can give rise to a full length-MAVS and a shorter isoform termed miniMAVS. In response to viral infections, viral RNA can be sensed by the cytosolic RNA sensors retinoic acid-inducible gene I (RIG-I) and/or melanoma differentiation-associated protein 5 (MDA5) and activate NF-κB through interaction with MAVS. MAVS can also sense cellular stress and activate an anti-oxidative stress (AOS) response through the activation of NF-κB. Because NF-κB is a main cellular transcription factor for HIV-1, we wanted to address what role MAVS plays in HIV-1 reactivation from latency in CD4 T cells. Our results indicate that RIG-I agonists required full length-MAVS whereas the AOS response induced by Dynasore through its catechol group can reactivate latent HIV-1 in a MAVS dependent manner through miniMAVS isoform. Furthermore, we uncover that PKC agonists, a class of latency-reversing agents, induce an AOS response in CD4 T cells and require miniMAVS to fully reactivate latent HIV-1. Our results indicate that the AOS response, through miniMAVS, can induce HIV-1 transcription in response to cellular stress and targeting this pathway adds to the repertoire of approaches to reactivate latent HIV-1 in ‘shock-and-kill’ strategies.

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Abstract P225: Rupp Rat Model Cd4+ T Cells Activate Nk Cells And Cause Mitochondrial Oxidative Stress And Hypertension In Normal Pregnant Rats

Hypertension ◽

10.1161/hyp.76.suppl_1.p225 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Evangeline M Deer ◽

Kristin Reeve ◽

Lorena M Amaral ◽

Venkata Ramana Vaka ◽

Michael Franks ◽

...

Keyword(s):

Oxidative Stress ◽

T Cells ◽

T Cell ◽

Nk Cells ◽

Rat Model ◽

Adoptive Transfer ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Pregnant Rats ◽

Atp Production

Preeclampsia (PE) is new onset hypertension during pregnancy and is associated with elevated inflammatory response such as CD4+ T cells, NK cells, and cytokines. We have previously shown women with PE exhibit increases in circulating and placental CD4+T cells and placental mitochondrial (mt) dysfunction/ROS compared to normal pregnant (NP) women. The Reduced Uterine Perfusion Pressure (RUPP) rat model produces many characteristics of PE such as hypertension, increases in CD4+ cells, increases in renal and placental NK cells, and mt dysfunction/ROS. We have previously demonstrated that RUPP CD4+T cells cause hypertension in NP rats, however the role of RUPP CD4+ T cells in stimulating NK cells to cause mt dysfunction/ROS are not elucidated. Therefore, we examined the effect of adoptive transfer of RUPP CD4+ T cells to activate NK cells in NP rats. Splenic CD4+ T cells were isolated from RUPP rats, cultured, and injected into NP rats on GD 13. On GD19, MAP values and blood/tissue samples were collected from both RUPP CD4+ T cell recipients and NP controls. Mitochondrial respiration and mtROS were measured in isolated mitochondria using the Oxygraph 2K and fluorescent microplate reader, respectively. A student’s t-test was used for statistical analysis. On GD19, MAP increased to 110±2 mmHg (n=13) in RUPP CD4+ T cell recipients compared to control NP rats 102±2 mmHg (n=7, p<0.05). Circulating cytolytic NK cells increased to 3±0.6% in RUPP CD4+ T cell recipients (n=8) compared to NP controls 0.3±0.2% (n=7, p<0.05). Placental state 3 (209.3±31.3 vs 422.7 ±83.3 pmol/sec/mg, p<0.05) and maximal (152.1±46.2 vs 229.7±58.9 pmol/sec/mg) and renal state 3 (133.4 ±21.4 vs 289.8±43.4 pmol/sec/mg, p<0.05) and maximal (61.8±18 vs 242.4±27.7 pmol/sec/mg, p<0.05) respiration rates, indicative of ATP production and electron transport chain efficacy respectively, were reduced with RUPP CD4+ T cells (n=6; n=9) compared to NP (n=5; n=5). Collectively, the data indicate that the adoptive transfer of RUPP CD4+ T cells stimulates cytolytic NK cells and placental and renal mitochondrial dysfunction/ROS during pregnancy as important mechanisms of hypertension in the pathophysiology of preeclampsia. Keywords: Preeclamspia, Hypertension, Oxidative stress

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CD4+ T cells epigenetically modified by oxidative stress cause lupus-like autoimmunity in mice

Journal of Autoimmunity ◽

10.1016/j.jaut.2015.06.004 ◽

2015 ◽

Vol 62 ◽

pp. 75-80 ◽

Cited By ~ 38

Author(s):

Faith M. Strickland ◽

YePeng Li ◽

Kent Johnson ◽

Zhichao Sun ◽

Bruce C. Richardson

Keyword(s):

Oxidative Stress ◽

T Cells ◽

Cd4 T Cells

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Characterization of Mitochondrial Bioenergetics in Preeclampsia

Journal of Clinical Medicine ◽

10.3390/jcm10215063 ◽

2021 ◽

Vol 10 (21) ◽

pp. 5063

Author(s):

Ramana Vaka ◽

Evangeline Deer ◽

Mark Cunningham ◽

Kristen M. McMaster ◽

Kedra Wallace ◽

...

Keyword(s):

Oxidative Stress ◽

T Cells ◽

Cd4 T Cells ◽

Type I ◽

Pregnant Rats ◽

Complex Iv ◽

Tnf Α ◽

Placental Ischemia

Preeclampsia (PE) is characterized by new onset hypertension during pregnancy and is associated with oxidative stress, placental ischemia, and autoantibodies to the angiotensin II type I receptor (AT1-AA). Mitochondrial (mt) dysfunction in PE and various sources of oxidative stress, such as monocytes, neutrophils, and CD4 + T cells, have been identified as important players in the pathophysiology of PE. We have established the significance of AT1-AA, TNF-α, and CD4 + T cells in causing mitochondrial (mt) dysfunction in renal and placental tissues in pregnant rats. Although the role of mt dysfunction from freshly isolated intact placental mitochondria has been compared in human PE and normally pregnant (NP) controls, variations among preterm PE or term PE have not been compared and mechanisms contributing to mt ROS during PE are unclear. Therefore, we hypothesized PE placentas would exhibit impaired placental mt function, which would be worse in preterm PE patients than in those of later gestational ages. Immediately after delivery, PE and NP patient’s placentas were collected, mt were isolated and mt respiration and ROS were measured. PE patients at either < or >34 weeks gestational age (GA) exhibited elevated blood pressure and decreased placental mt respiration rates (state 3 and maximal). Patients delivering at >34 weeks exhibited decreased Complex IV activity and expression. Placental mtROS was significantly reduced in both PE groups, compared to NP placental mitochondria. Collectively, the study demonstrates that PE mt dysfunction occurs in the placenta, with mtROS being lower than that seen in NP controls. These data indicate why antioxidants, as a potential target or new therapeutic agent, may not be ideal in treating the oxidative stress associated with PE.

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Oxidative Stress Induces Mitochondrial Compromise in CD4 T Cells From Chronically HCV-Infected Individuals

Frontiers in Immunology ◽

10.3389/fimmu.2021.760707 ◽

2021 ◽

Vol 12 ◽

Author(s):

Madison Schank ◽

Juan Zhao ◽

Ling Wang ◽

Lam Ngoc Thao Nguyen ◽

Dechao Cao ◽

...

Keyword(s):

Oxidative Stress ◽

T Cells ◽

Mitochondrial Dna ◽

Cd4 T Cells ◽

Hcv Infection ◽

Cellular Respiration ◽

Peroxisome Proliferator ◽

Mtdna Copy Number ◽

Mitochondrial Mass ◽

Mitochondrial Functions

We have previously shown that chronic Hepatitis C virus (HCV) infection can induce DNA damage and immune dysfunctions with excessive oxidative stress in T cells. Furthermore, evidence suggests that HCV contributes to increased susceptibility to metabolic disorders. However, the underlying mechanisms by which HCV infection impairs cellular metabolism in CD4 T cells remain unclear. In this study, we evaluated mitochondrial mass and intracellular and mitochondrial reactive oxygen species (ROS) production by flow cytometry, mitochondrial DNA (mtDNA) content by real-time qPCR, cellular respiration by seahorse analyzer, and dysregulated mitochondrial-localized proteins by Liquid Chromatography-Mass Spectrometry (LC-MS) in CD4 T cells from chronic HCV-infected individuals and health subjects. Mitochondrial mass was decreased while intracellular and mitochondrial ROS were increased, expressions of master mitochondrial regulators peroxisome proliferator-activated receptor 1 alpha (PGC-1α) and mitochondrial transcription factor A (mtTFA) were down-regulated, and oxidative stress was increased while mitochondrial DNA copy numbers were reduced. Importantly, CRISPR/Cas9-mediated knockdown of mtTFA impaired cellular respiration and reduced mtDNA copy number. Furthermore, proteins responsible for mediating oxidative stress, apoptosis, and mtDNA maintenance were significantly altered in HCV-CD4 T cells. These results indicate that mitochondrial functions are compromised in HCV-CD4 T cells, likely via the deregulation of several mitochondrial regulatory proteins.

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Effect of Chronic Oxidative Stress on Neuroinflammatory Response Mediated by CD4+T Cells in Neurodegenerative Diseases

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2018.00114 ◽

2018 ◽

Vol 12 ◽

Cited By ~ 84

Author(s):

Helena Solleiro-Villavicencio ◽

Selva Rivas-Arancibia

Keyword(s):

Oxidative Stress ◽

T Cells ◽

Neurodegenerative Diseases ◽

Cd4 T Cells ◽

Neuroinflammatory Response ◽

Chronic Oxidative Stress

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Impaired base excision repair and accumulation of oxidative base lesions in CD4+ T cells of HIV-infected patients

Blood ◽

10.1182/blood-2004-11-4272 ◽

2005 ◽

Vol 105 (12) ◽

pp. 4730-4735 ◽

Cited By ~ 33

Author(s):

Pål Aukrust ◽

Luisa Luna ◽

Thor Ueland ◽

Rune F. Johansen ◽

Fredrik Müller ◽

...

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

T Cells ◽

Hiv Infection ◽

Base Excision Repair ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Oxidative Dna Damage ◽

Excision Repair ◽

Base Excision

Abstract Several studies have reported enhanced oxidative stress in patients with HIV infection. An important pathophysiologic consequence of increased oxidative stress is endogenous DNA damage, and the base excision repair pathway is the most important mechanism to withstand such deleterious effects. To investigate the role of base excision repair in HIV infection, we examined 7,8-dihydro-8-oxoguanine (8-oxoG) levels as a marker of oxidative DNA damage and DNA glycosylase activities in CD4+ and CD8+ T cells of HIV-infected patients and controls. These results showed that the HIV-infected patients, particularly those with advanced disease, had increased levels of 8-oxoG in CD4+ T cells and marked declines in DNA glycosylase activity for the repair of oxidative base lesions in these cells. In contrast, CD8+ T cells from HIV-infected patients, with 8-oxoG levels similar to those in healthy controls, showed enhanced capacity to repair oxidative DNA damage. Finally, highly active antiretroviral therapy induced increased glycosylase activity in CD4+ T cells and normalized 8-oxoG levels. This imbalance between the accumulation of oxidative DNA damage and the capacity to repair such lesions in CD4+ T cells may represent a previously unrecognized mechanism involved in the numerical and functional impairment of CD4+ T cells in patients with HIV infection. (Blood. 2005; 105:4730-4735)

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