Splenocyte transfer from hypertensive donors eliminates premenopausal female protection from Ang II-induced hypertension

2022 ◽  
Author(s):  
Megan A Sylvester ◽  
Dennis P Pollow ◽  
Caitlin Moffett ◽  
Wendy Nunez ◽  
Jennifer L Uhrlaub ◽  
...  
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
Adoptive Transfer ◽  
T Regulatory Cells ◽  
Estrogen Signaling ◽  
Ang Ii ◽  
Regulatory Cells ◽  
Adaptive Immune Cells ◽  
Induced Hypertension ◽  
Rag 1

Premenopausal females are protected from Angiotensin II (Ang II)-induced hypertension following the adoptive transfer of T cells from normotensive donors. For the present study, we hypothesized that the transfer of hypertensive T cells (HT) or splenocytes (HS) from hypertensive donors would eliminate premenopausal protection from hypertension. Premenopausal Rag-1-/- females received either normotensive (NT) or hypertensive cells, three weeks prior to Ang II infusion (14 days, 490 ng/kg/min). Contrary to our hypothesis, no increase in Ang II-induced blood pressure was observed in the NT/Ang or HT/Ang groups. Flow cytometry demonstrated that renal FoxP3+ T regulatory cells were significantly decreased and IHC showed an increase in renal F4/80+ macrophages in HT/Ang, suggesting a shift in the renal inflammatory environment despite no change in blood pressure. Renal mRNA expression of MCP-1, Endothelin-1, GPER-1 were significantly decreased in HT/Ang. The adoptive transfer of hypertensive splenocytes prior to Ang II infusion (HS/Ang) eliminated premenopausal protection from hypertension and significantly decreased splenic FoxP3+ T regulatory cells compared to females receiving normotensive splenocytes (NS/Ang). Expression of MIP-1a/CCL3, a potent macrophage chemokine was elevated in HS/Ang, however no increase in renal macrophage infiltration occurred. Together, these data show that in premenopausal females T cells from hypertensive donors are not sufficient to induce a robust Ang II mediated hypertension, in contrast, transfer of hypertensive splenocytes (consisting of T/B lymphocytes, dendritic cells, macrophages) is sufficient. Further work is needed to understand how innate and adaptive immune cells and estrogen signaling coordinate to cause differential hypertensive outcomes in premenopausal females.

scholarly journals Menopause and FOXP3+ Treg cell depletion eliminate female protection against T cell-mediated angiotensin II hypertension

2019 ◽  
Vol 317 (2) ◽  
pp. H415-H423 ◽  
Author(s):  
Dennis P. Pollow ◽  
Joshua A. Uhlorn ◽  
Megan A. Sylvester ◽  
Melissa J. Romero-Aleshire ◽  
Jennifer L. Uhrlaub ◽  
...  
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
T Cell ◽  
Angiotensin Ii ◽  
Systolic Blood Pressure ◽  
T Regulatory Cells ◽  
Ang Ii ◽  
Regulatory Cells ◽  
Rag 1 ◽  
Blood Pressure Responses

Although it is known that the prevalence and severity of hypertension increases in women after menopause, the contribution of T cells to this process has not been explored. Although the immune system is both necessary and required for the development of angiotensin II (ANG II) hypertension in men, we have demonstrated that premenopausal women are protected from T cell-mediated hypertension. The goal of the current study was to test the hypotheses that 1) female protection against T cell-mediated ANG II hypertension is eliminated following progression into menopause and 2) T regulatory cells (Tregs) provide premenopausal protection against ANG II-induced hypertension. Menopause was induced in Rag-1−/− mice (via 4-vinylcyclohexene diepoxide), and all mice received a 14-day ANG II infusion. Donor CD3+ T cells were adoptively transferred 3 wk before ANG II infusion. In the absence of T cells, systolic blood pressure responses to ANG II were similar to those seen in premenopausal mice (Δ12 mmHg). After adoptive transfer of T cells, ANG II significantly increased systolic blood pressure in postmenopausal females (Δ28 mmHg). A significant increase in F4/80 positive renal macrophages, an increase in renal inflammatory gene expression, along with a reduction in renal expression of mannose receptor C-type 1, a marker for M2 macrophages, accompanied the increase in systolic blood pressure (SBP). Flow cytometric analysis identified that Tregs were significantly decreased in the spleen and kidneys of Rag-1−/− menopausal mice versus premenopausal females, following ANG II infusion. In a validation study, an anti-CD25 antibody was used to deplete Tregs in premenopausal mice, which induced a significant increase in SBP. These results demonstrate that premenopausal protection against T cell-mediated ANG II hypertension is eliminated once females enter menopause, suggesting that a change in hormonal status upregulates macrophage-induced proinflammatory and T cell-dependent responses. Furthermore, we are the first to report that the presence of Tregs are required to suppress ANG II hypertension in premenopausal females. NEW & NOTEWORTHY Whether progression into menopause eliminated female protection against T cell-mediated hypertension was examined. Menopausal mice without T cells remained protected against angiotensin II (ANG II) hypertension; however, in the presence of T cells, blood pressure responses to ANG II increased significantly in menopause. Underlying mechanisms examined were anti-inflammatory protection provided by T regulatory cells in premenopausal females and renal inflammatory processes involving macrophage infiltration and cytokine activation.

Abstract P618: Foxp3+ Regulatory T cell Depletion Eliminates Ang II-Induced Hypertension Resistance in Female Mice

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Dennis Pollow ◽  
Melissa J Romero-Aleshire ◽  
Jennifer Uhrlaub ◽  
John P Konhilas ◽  
Janko Nikolich-Zugich ◽  
...  
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
T Cell ◽  
T Regulatory Cells ◽  
Flow Cytometric Analysis ◽  
Ang Ii ◽  
Regulatory Cells ◽  
T Effector Cells ◽  
Female Mice ◽  
Cell Counts

Compared to males, premenopausal females are resistant to the development of Ang II hypertension. In males, Ang II induces hypertension, in part, through mechanisms requiring T effector lymphocytes. Recently, our lab has demonstrated that females can prevent the T lymphocyte-dependent increase in blood pressure (SBP and MAP) and expression of pro-inflammatory cytokines in the kidney in response to Ang II infusion. Because Foxp3 + T regulatory cells suppress the pro-inflammatory and hypertensive actions of T effector cells, we sought to determine whether Foxp3 + T regulatory cells contribute to this resistance in females. Premenopausal (8 week old) 129SVE female mice were infused with Ang II (800ng/kg/min, 14d) and received 4 doses of the anti-CD25 antibody PC-61 to transiently deplete Foxp3 + T regulatory cells (every 84 hours beginning 12 hours prior to Ang II infusion, 250μg/dose, i.p., vehicle control). Blood pressure was measured before and after Ang II infusion via non-invasive tail cuff. Ang II induced a significant increase in systolic blood pressure in Foxp3 + -depleted mice, while resistance was retained in vehicle-treated mice (Con Δ5 ± 5mmHg, Ang II Δ10 ± 7mmHg, PC-61 Δ28 ± 9 * mmHg, * p<0.05 vs Con). Flow cytometric analysis demonstrated that PC-61-treatment significantly reduced the number of Foxp3 + splenic T cells compared to control (Con 1.7x10 6 cells, Ang II 2.3x10 6 cells, PC-61 8.3x10 5* cells, * P<0.05 vs Con) without changing CD3 + and CD4 + T cell counts. The number of Foxp3 + T cells residing in the kidney was also significantly reduced by PC-61 (Con 1,152 ± 368 cells, Ang II 686 ± 389 cells, PC-61 210 ± 35 * cells, * P<0.05 vs Con). Quantitative real-time PCR demonstrated that whole kidney expression of MCP-1 and ENaC alpha were significantly increased in Foxp3 + -depleted mice (MCP-1- Con 1.0 ± 0.1, Ang II 1.6 ± 0.4, PC-61 1.8 ± 0.2 * ; ENaC-α- Con 1.0 ± 0.1, Ang II 1.6 ± 0.2, PC-61 2.1 ± 0.1 * , * P<0.05 vs Con). These data suggest that the anti-inflammatory Foxp3 + T regulatory cells play a significant role in mediating the resistance to Ang II hypertension in premenopausal female mice, and may influence renal inflammation and sodium retention during chronic Ang II infusion.

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.

scholarly journals Greater T Regulatory Cells in Females Attenuate DOCA-Salt–Induced Increases in Blood Pressure Versus Males

Hypertension ◽  
2020 ◽  
Vol 75 (6) ◽  
pp. 1615-1623 ◽  
Author(s):  
Kasey M. Belanger ◽  
G. Ryan Crislip ◽  
Ellen E. Gillis ◽  
Mahmoud Abdelbary ◽  
Jacqueline B. Musall ◽  
...  
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
T Regulatory Cells ◽  
Critical Role ◽  
Kidney Injury ◽  
Male Rats ◽  
Regulatory Cells ◽  
Salt Treatment ◽  
Males And Females ◽  
The Impact

Hypertension is the most common risk factor for cardiovascular disease, causing over 18 million deaths a year. Although the mechanisms controlling blood pressure (BP) in either sex remain largely unknown, T cells play a critical role in the development of hypertension. Further evidence supports a role for the immune system in contributing to sex differences in hypertension. The goal of the current study was to first, determine the impact of sex on the renal T-cell profiles in DOCA-salt hypertensive males and females and second, test the hypothesis that greater numbers of T regulatory cells (Tregs) in females protect against DOCA-salt–induced increases in BP and kidney injury. Male rats displayed greater increases in BP than females following 3 weeks of DOCA-salt treatment, although increases in renal injury were comparable between the sexes. DOCA-salt treatment resulted in an increase in proinflammatory T cells in both sexes; however, females had more anti-inflammatory Tregs than males. Additional male and female DOCA-salt rats were treated with anti-CD25 to decrease Tregs. Decreasing Tregs significantly increased BP only in females, thereby abolishing the sex difference in the BP response to DOCA-salt. This data supports the hypothesis that Tregs protect against the development of hypertension and are particularly important for the control of BP in females.

scholarly journals Female spontaneously hypertensive rats have greater renal anti-inflammatory T lymphocyte infiltration than males

2012 ◽  
Vol 303 (4) ◽  
pp. R359-R367 ◽  
Author(s):  
Ashlee J. Tipton ◽  
Babak Baban ◽  
Jennifer C. Sullivan
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
T Cell ◽  
Spontaneously Hypertensive Rats ◽  
T Regulatory Cells ◽  
Dependent Manner ◽  
Regulatory Cells ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Cell Profile

T cells contribute to hypertension in male experimental models; data in females is lacking even though women are more likely to develop immune disorders. The goal of this study was to determine whether immune cells contribute to hypertension in female spontaneously hypertensive rats (SHR) and define the T cell profile in whole blood and kidneys of male and female SHR. We hypothesized that inflammatory cells contribute to hypertension in female SHR; however, male SHR have a higher blood pressure so we hypothesize they will have a heightened inflammatory profile. The lymphocyte inhibitor mycophenolate mofetil (MMF) was administered in a dose-dependent manner to SHR. At the highest dose (50 mg·kg−1·day−1), blood pressure was significantly decreased in both sexes, yet the percent decrease in blood pressure was greater in females (female: 12 ± 1%; males: 7 ± 1%, P = 0.01). Circulating and renal T cell profiles were defined using analytical flow cytometry. Female SHR had more circulating CD3+, CD4+, and pro-inflammatory CD3+CD4+RORγ+ Th17 cells, whereas males had more immune-suppressive CD3+CD4+Foxp3+ T regulatory cells. In the kidney, females had greater numbers of CD8+ and T regulatory cells than males, whereas males had greater CD4+ and Th17 cell infiltration. MMF decreased circulating and renal T cells in both sexes ( P < 0.0001), although the effect of MMF on T cell subtypes was sex specific with females having greater sensitivity to MMF-induced decreases in lymphocytes. In conclusion, there is a lymphocyte contribution to the maintenance of hypertension in the female SHR and sex of the animal impacts the T cell profile.

Abstract P137: Knock Out Of Regulatory G Protein Signaling 2 Specifically In CD4 T Cells Prevents Angiotensin II Induced Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Sabrina M Scroggins ◽  
Gabrielle Gray ◽  
Monica C Myers ◽  
Sarah N Miller ◽  
Pablo Nakagawa ◽  
...  
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
G Protein ◽  
Inflammatory Cytokines ◽  
Cd4 T Cells ◽  
G Protein Signaling ◽  
Ang Ii ◽  
Protein Signaling ◽  
Induced Hypertension ◽  
Anti Inflammatory

Preeclampsia (PreE) is a hypertensive disorder in pregnancy. Aberrations of Regulator of G protein Signaling (RGS) family members are associated with PreE and hypertension (HTN). We previously observed a 9-fold increase in RGS2 in CD4+ T cells during PreE. In total, our work suggests that modulating T cells may be a therapeutic strategy for HTN. We hypothesize that reducing RGS2 specifically in CD4+ T cells will restore anti-inflammatory T cell responses and prevent HTN. Utilizing an angiotensin (ANG) II infusion mouse model, we aimed to investigate 1) the impact of the loss of RGS2 in CD4+ T cells on cytokine production and 2) if the loss of RGS2 in CD4+ T cells will protect against the development of HTN. RGS2 was knocked-out in CD4+ T cells (CD4-Cre x RGS2 flox mice; KO ). CD4 RGS2 KO (n=5) or littermate control mice (CTL, n=3) were administered 490 ng/kg/min ANG II for 21 days via mini-osmotic pump. Blood pressure was assessed by radiotelemetry. ELISAs were performed to determine pro- and anti- inflammatory cytokine levels in tissues from KO (n=9) and CTL (n=8) mice. Pro-inflammatory cytokines IFNγ and IL-17 were not significantly different in the heart, kidney, liver or spleen of KO vs CTL mice. The anti-inflammatory cytokines IL-4 (KO 410 vs CTL 339 pg/mL, p<0.05) and TGFβ (KO 5.7x10 5 vs 5.0x10 5 pg/mL, p<0.05) were increased in the kidneys of KO mice compared to CTL mice. At baseline, KO and CTL mice showed no differences in 24-hr heart rate (HR), systolic or diastolic blood pressure (SBP and DBP, respectively). Throughout the study, KO mice had a significantly lower 24-hr SBP (Day 7: KO 132.3 vs CTL 149.7 mmHg, p<0.05; Day 14: KO 123.6 vs CTL 162.3 mmHg, p<0.05; Day 21: KO 118.3 vs 154.8 mmHg, p<0.05) and DBP (Day 7: KO 101.2 vs CTL 113.8 mmHg, p<0.05; Day 14: KO 98.4 vs CTL 121.8 mmHg, p<0.05; Day 21: KO 96.8 vs 116.4 mmHg, p<0.05) compared to CTL mice. The 24-hr HR was only significantly lower at three weeks ANG II (KO 493.4 vs CTL 540.6 bpm, p<0.05) compared to CTL mice. The increased levels of IL-4 and TGFβ observed in KO mice support a role of RGS2 in anti-inflammatory immune responses. In accordance with our hypothesis, the loss of RGS2, specifically in CD4+ T cells prevented ANG II-induced hypertension. Therefore, RGS2 expression in CD4+ T cells plays a critical role in the development of HTN.

Abstract 098: Foxp3+ T Regulatory Lymphocytes Counteract Angiotensin Ii-induced Vascular Injury

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Muhammad Oneeb Rehman Mian ◽  
Tlili Barhoumi ◽  
Marie Briet ◽  
Adriana Cristina Ene ◽  
Asia Rehman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Endothelial Dysfunction ◽  
Vascular Injury ◽  
Adoptive Transfer ◽  
Ros Production ◽  
Ang Ii ◽  
Fibronectin Expression ◽  
Induced Hypertension ◽  
Regulatory Lymphocytes

Objective: T effector lymphocytes contribute to vascular injury in angiotensin (Ang) II-induced hypertension, but the role of T regulatory lymphocytes (Tregs) is unclear. Ang II-induced hypertension is blunted in T and B lymphocyte-deficient (Rag1-/-) mice, and restored with reconstitution of T cells. We hypothesized that adoptive transfer of FOXP3-deficient Scurfy (Sf) vs. wild-type (WT) T cells will exacerbate Ang II-induced vascular damage in Rag1-/- mice. Methods: Eleven-week old male Rag1-/- mice were injected IV with vehicle, 10 million WT or Sf T cells, 1 million CD4+CD25+ Tregs alone or with Sf T cells, and 2 weeks later were infused or not with Ang II (490 ng/kg/min, SC) for 14 days (n=3-8). Telemetric BP, vascular function and structure, and reactive oxygen species (ROS) production and fibronectin expression in mesenteric arteries (MA) were determined. Results: Ang II induced a 40 mmHg systolic BP rise in all the groups, but diastolic BP rise was ~10 mmHg greater in WT and Sf T cell-injected mice than in controls (P<0.01). Treg injection alone or with Sf T cells prevented or delayed by 7 days the BP rise, respectively (P<0.05). Ang II did not induce endothelial dysfunction in vehicle or Treg only-injected mice. Adoptive transfer of WT T cells restored Ang II induced-endothelial dysfunction (60±5% vs. 83±4%, P<0.05), which was exaggerated in Sf T cell-injected mice (56±6% vs. 97±7%, P<0.01), but reduced by Treg co-injection (74±4%, P<0.05). Ang II increased ROS production in MA wall (239±32% vs. 119±20%) and perivascular fat (369±39% vs. 84±8%) in Sf T cell-injected mice (P<0.01), but not when co-injected with Tregs. Ang II induced increased vascular stiffness (P<0.01) and media/lumen (M/L, P<0.05) in vehicle (strain at 140 mmHg: 0.60±0.02 vs. 0.80±0.02; M/L: 4.1±0.2 vs. 2.9±0.2%) and Sf T cell-injected mice (strain at 140 mmHg: 0.63±0.01 vs. 0.89±0.04; M/L: 4.7±0.3 vs. 2.9±0.1%). Ang II increased MA fibronectin expression (P<0.01) in vehicle (113±12 vs. 51±14 RFU/μm2) and Sf T cell-injected mice (85±7 vs. 36±9 RFU/μm2). Conclusion: These results demonstrate that Foxp3+ Tregs have a protective role against Ang II-induced vascular dysfunction, remodeling and oxidative stress.

scholarly journals Multiple sclerosis patients have reduced resting and increased activated CD4+CD25+FOXP3+T regulatory cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nirupama D. Verma ◽  
Andrew D. Lam ◽  
Christopher Chiu ◽  
Giang T. Tran ◽  
Bruce M. Hall ◽  
...  
Keyword(s):  
T Cells ◽  
T Regulatory Cells ◽  
Mononuclear Cells ◽  
Effector Memory ◽  
Regulatory Cells ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Treg Population ◽  
Multiple Sclerosis Patients ◽  
Population Iii

AbstractResting and activated subpopulations of CD4+CD25+CD127loT regulatory cells (Treg) and CD4+CD25+CD127+ effector T cells in MS patients and in healthy individuals were compared. Peripheral blood mononuclear cells isolated using Ficoll Hypaque were stained with monoclonal antibodies and analysed by flow cytometer. CD45RA and Foxp3 expression within CD4+ cells and in CD4+CD25+CD127loT cells identified Population I; CD45RA+Foxp3+, Population II; CD45RA−Foxp3hi and Population III; CD45RA−Foxp3+ cells. Effector CD4+CD127+ T cells were subdivided into Population IV; memory /effector CD45RA− CD25−Foxp3− and Population V; effector naïve CD45RA+CD25−Foxp3−CCR7+ and terminally differentiated RA+ (TEMRA) effector memory cells. Chemokine receptor staining identified CXCR3+Th1-like Treg, CCR6+Th17-like Treg and CCR7+ resting Treg. Resting Treg (Population I) were reduced in MS patients, both in untreated and treated MS compared to healthy donors. Activated/memory Treg (Population II) were significantly increased in MS patients compared to healthy donors. Activated effector CD4+ (Population IV) were increased and the naïve/ TEMRA CD4+ (Population V) were decreased in MS compared to HD. Expression of CCR7 was mainly in Population I, whereas expression of CCR6 and CXCR3 was greatest in Populations II and intermediate in Population III. In MS, CCR6+Treg were lower in Population III. This study found MS is associated with significant shifts in CD4+T cells subpopulations. MS patients had lower resting CD4+CD25+CD45RA+CCR7+ Treg than healthy donors while activated CD4+CD25hiCD45RA−Foxp3hiTreg were increased in MS patients even before treatment. Some MS patients had reduced CCR6+Th17-like Treg, which may contribute to the activity of MS.

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