Abstract P209: Loss Of Rgs2 Specifically In CD4+ T Cells Decreases The Hypertensive Response To Vasopressin

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Sabrina M Scroggins ◽  
Gabrielle Gray ◽  
Douglas G Scroggins ◽  
Kamara S Shaw ◽  
Donna A Santillan ◽  
...  
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
Transforming Growth Factor Beta ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Interleukin 4 ◽  
Hypertensive Disorder ◽  
Pressure System ◽  
Vasopressin Infusion ◽  
Induced Hypertension

Regulator of G protein Signaling (RGS) family members can modulate multiple cardiovascular hormones and are associated with hypertension and preeclampsia, a hypertensive disorder in pregnancy. We previously observed a 9-fold increase in RGS2 in CD4+ T cells isolated from women with preeclampsia compared to normotensive women. Further, in non-pregnant mice, we showed that loss of RGS2 in CD4+ T cells prevented angiotensin II-induced hypertension (measured via radiotelemetry) and resulted in increased levels of the anti-inflammatory cytokines interleukin 4 and transforming growth factor beta. We hypothesize that modulating RGS2 in CD4+ T cells may be a therapeutic strategy for hypertension. The objective of this study was to determine if loss of RGS2 specifically in CD4+ T cells protects against the development of arginine vasopressin-induced hypertension in mixed background CD4+ RGS2 knockout mice (CD4 RGS2 KO ). To generate mice wherein RGS2 is specifically knocked out in CD4+ T cells, CD4-Cre+ mice (C57BL/6J) were crossed with RGS2 flox/flox mice (B6SJLF1/J). Female 8-12 week old CD4 RGS2 KO or littermate control mice (n=5 per group) from this mixed strain were administered 24 ng/hr vasopressin for 21 days via mini-osmotic pump. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MP), and heart rate (HR) were assessed using a high throughput non-invasive blood pressure system. Prior to vasopressin infusion, KO and CTL mice showed no differences in SBP, DBP, MP, or HR. At 9-13 days of vasopressin-infusion, KO mice had a significantly lower 24-hr SBP [KO 138.7 ±4.7 vs CTL 155.9 ±3.4 mmHg, p<0.05], DBP [KO 106.9 ±4.1 vs CTL 122.8 ±2.9 mmHg, p<0.05], MP [KO 117.2 ±4.3 vs CTL 133.5 ±3.0 mmHg, p<0.05], and HR [KO 378 ±18.7 vs CTL 445 x±12.8 BPM, p<0.05] compared to CTL mice. Here, we demonstrate that in a mixed strain CD4+ RGS2 KO mouse, loss of RGS2 specifically in CD4+ T cells prevented vasopressin-induced hypertension. Therefore, RGS2 expression in CD4+ T cells may play an expanded role in the modulation of hypertension.

scholarly journals The transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper cells and isotype-switched antibody responses in the lung mucosa

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Heather D Marshall ◽  
John P Ray ◽  
Brian J Laidlaw ◽  
Nianzhi Zhang ◽  
Dipika Gawande ◽  
...  
Keyword(s):  
T Cells ◽  
Transforming Growth Factor Beta ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Antibody Responses ◽  
T Follicular Helper Cells ◽  
High Affinity ◽  
Tfh Cells ◽  
Helper Cells ◽  
Follicular Helper

T follicular helper cells (Tfh) are crucial for the initiation and maintenance of germinal center (GC) reactions and high affinity, isotype-switched antibody responses. In this study, we demonstrate that direct TGF-β signaling to CD4 T cells is important for the formation of influenza-specific Tfh cells, GC reactions, and development of isotype-switched, flu-specific antibody responses. Early during infection, TGF-β signaling suppressed the expression of the high affinity IL-2 receptor α chain (CD25) on virus-specific CD4 T cells, which tempered IL-2 signaling and STAT5 and mammalian target of rapamycin (mTOR) activation in Tfh precursor CD4 T cells. Inhibition of mTOR allowed for the differentiation of Tfh cells in the absence of TGF-βR signaling, suggesting that TGF-β insulates Tfh progenitor cells from IL-2-delivered mTOR signals, thereby promoting Tfh differentiation during acute viral infection. These findings identify a new pathway critical for the generation of Tfh cells and humoral responses during respiratory viral infections.

scholarly journals Peripheral Autoantigen Induces Regulatory T Cells that Prevent Autoimmunity

1999 ◽  
Vol 189 (5) ◽  
pp. 877-882 ◽  
Author(s):  
Benedict Seddon ◽  
Don Mason
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Adoptive Transfer ◽  
Autoimmune Thyroiditis ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Thyroid Autoimmunity ◽  
Interleukin 4 ◽  
Common Mechanism ◽  
Antigen Specificity

Previous studies have shown that autoimmune thyroiditis can be induced in normal laboratory rats after thymectomy and split dose γ-irradiation. Development of disease can be prevented by reconstitution of PVG rats shortly after their final irradiation with either peripheral CD4+CD45RC− T cells or CD4+CD8− thymocytes from syngeneic donors. Although the activity of both populations is known to depend on the activities of endogenously produced interleukin 4 and transforming growth factor β, implying a common mechanism, the issue of antigen specificity of the cells involved has not yet been addressed. In this study, we show that the regulatory T cells that prevent autoimmune thyroiditis are generated in vivo only when the relevant autoantigen is also present. Peripheral CD4+ T cells, from rats whose thyroids were ablated in utero by treatment with 131I, were unable to prevent disease development upon adoptive transfer into thymectomized and irradiated recipients. This regulatory deficit is specific for thyroid autoimmunity, since CD4+ T cells from 131I-treated PVG.RT1u rats were as effective as those from normal donors at preventing diabetes in thymectomized and irradiated PVG.RT1u rats. Significantly, in contrast to the peripheral CD4+ T cells, CD4+CD8− thymocytes from 131I-treated PVG donors were still able to prevent thyroiditis upon adoptive transfer. Taken together, these data indicate that it is the peripheral autoantigen itself that stimulates the generation of the appropriate regulatory cells from thymic emigrant precursors.

Reduced Levels of mTOR and TGF- β Signaling Pathway-Associated Proteins in Patients with High Risk MDSsamia AL-Shouli. , Pilar Perezabellan, Frederic Toulza. Shahram Kordasti, Ghulam Mufti

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5501-5501
Author(s):  
Samia Towfeek Al-Shouli ◽  
Ghulam J Mufti
Keyword(s):  
T Cells ◽  
High Risk ◽  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Conflicts Of Interest ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Related Proteins

Abstract Background: T cell mediated immune dysregulation is an important feature of MDS. The expansion of regulatory T cells (Tregs) is one of the important factors in the progression of intermediate/high risk myelodysplastic syndrome (MDS) to acute myeloid leukemia. However, the exact mechanism for the expansion of Tregs in MDS is not known. Intracellular complements (particularly C3a and C5a) play a crucial role in the polarization of CD4+ T cells toward regulatory or effector phenotypes through Transforming growth factor-beta (TGF-β) pathway (C5aR2 mediated) or Mammalian Target of Rapamycin (mTOR)(C5aR mediated) respectively. The aim of this study was to investigate the potential role of mTOR and Akt as important proteins in complement related polarization of CD4+ T cells toward pro-inflammatory T helper cells in MDS. We have also studied the TGF-β signaling pathway related proteins, which are crucial for the expansion of Tregs. We investigated the level of TGF- β related proteins (phosphorylated (p) SMADs), as well as mTORc and Akt (Ser473) in high risk MDS and healthy donors (HD) before and after stimulation with CD3 and CD46 as a complement related co-stimulatory molecule. Methods: Peripheral blood mononuclear cell (PBMCs) from healthy controls and high-risk MDS patients were used for this study. Anti-CD3 (2.0 µg/mL), anti-CD28 (3.0 µg/mL) and/or anti-CD46 (2.0 µg/mL) antibodies were used to stimulate cells. The total protein was extracted by Bicinchoninic Acid (BCA) assay and quantified by nano-drop. The MILLIPLEX MAP Human TGF-β Signaling Magnetic Bead Panel 6-plex was used to detect the signaling changes in cell lysates using the Luminex® system following the manufacturer's instructions. Data were analysed using Microsoft Excel and expressed in means and standards deviation. The students T-test were used to assess the difference in means between groups. Results: TGF-β signaling pathway proteins pSMAD2, pSMAD3 and pSMAD4 as well as mTORc were evaluated. Unstimulated PBMCs from high-risk MDS patients showed a significantly lower level of m-TOR (p=0.01), pSMAD2 (p=0.01), pSMAD3 (p=0.02) and pSMAD4 (p=0.044) as compared to healthy donors. Following stimulation with anti-CD3±CD46 for 24 hours, there was no significant increase in protein levels of mTORc or Akt. However, in high-risk MDS patients the level of pSMAD2 (p=0.02) and pSMAD4 (p=0.006) remain significantly lower than healthy donors after 24 hours of stimulation with anti-CD3 and CD46. An aliquot of cells were used for flowcytometry following stimulation. Interestingly Tregs phenotype CD4+CD25highCD127lowexpressed higher level of intracellular C5aR2 in MDS (n=5) compared to HD (n=5). Conclusion: mTORc protein level in MDS is reduced and does not change in response to complement receptor stimulation neither does the level of Akt. This may prevent T cells to polarize toward pro-inflammatory T cells (Th1 or Th17) therefore avert an effective immune-surveillance against malignant clone. Lack of response to complement related co-stimulation and increase in C5aR2 expression suggest a potential mechanism for Treg expansion in MDS. These findings may lead to identification of new therapeutic targets in MDS, although need further studies on larger cohort of patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals The combination of Astragalus membranaceus extract and ligustrazine to improve the inflammation in rats with thrombolytic cerebral ischemia

2019 ◽  
Vol 33 ◽  
pp. 205873841986905 ◽  
Author(s):  
Ruihuan Pan ◽  
Mingchao Zhou ◽  
Yiping Zhong ◽  
Jingping Xie ◽  
Shanshan Ling ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Neurological Function ◽  
Interleukin 4 ◽  
Astragalus Membranaceus ◽  
Interleukin 17 ◽  
Lesion Volume ◽  
Combination Drug

The purpose of the study was to evaluate the effect of Astragalus membranaceus extract and ligustrazine combination on ameliorating inflammation in cerebral ischemic rats that have undergone thrombolysis. Astragalus membranaceus and ligustrazine per se, or a combination of A. membranaceus and ligustrazine was administered by intraperitoneal injection immediately after surgery and sham surgery. After the induction of thrombolysis, the neurological function was measured and cerebral lesion volume was determined. The regulatory T cells in the spleen were measured by flow cytometry. To explore the protective effects of the combination drug on the neurological function and inflammation, the expression of transcription factor Foxp3 and cytokines, including transforming growth factor beta 1, interleukin 10, interleukin 4, interleukin 1 beta, interferon gamma, interleukin 17, in damaged brain was examined using reverse transcription polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. The cerebral lesion volume was markedly reduced in the combination drug–treated rats compared to the rats treated with either A. membranaceus or ligustrazine alone ( P < 0.05). The neurological function, regulatory T cells, transcription factor Foxp3, transforming growth factor beta 1, interleukin 10, and interleukin 4 were markedly elevated in the rats treated with combination drugs ( P < 0.05). The expression of interleukin 1 beta, interferon gamma, and interleukin 17 was reduced in the rats treated with combination drug therapy ( P < 0.05). Treatment with a combination of A. membranaceus and ligustrazine can ameliorate inflammation after thrombolysis and regulate the related cytokines by elevating the expression of endogenous regulatory T cells.

scholarly journals Temporal Dynamics of T Helper Populations in the Proximal Small Intestine after Oral Bovine Lactoferrin Administration in BALB/c Mice

Nutrients ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 2852
Author(s):  
Mario Ynga-Durand ◽  
Gabriela Tapia-Pastrana ◽  
Xóchitl Abril Rebollar-Ruíz ◽  
Mariazell Yépez-Ortega ◽  
Oscar Nieto-Yañez ◽  
...  
Keyword(s):  
T Cells ◽  
Small Intestine ◽  
Transforming Growth Factor Beta ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Temporal Dynamics ◽  
Saline Control ◽  
Bovine Lactoferrin ◽  
Intestinal Immunity ◽  
Proximal Small Intestine

Bovine lactoferrin (bLf), a component of milk and a dietary supplement, modulates intestinal immunity at effector and inductor sites. Considering the regional difference in intestinal compartments and the dynamics of local cytokine-producing cells in the gut across time, the aim of this work was to characterize the effects of bLf on the proximal small intestine in a BALB/c murine model of oral administration. Male BALB/c mice were treated with oral bLf vs. saline control as mock by buccal deposition for 28 days. Intestinal secretions were obtained at different time points and cells were isolated from Peyer’s patches (PP) and lamina propria (LP) of the proximal small intestine as representative inductor and effector sites, respectively. Total and specific anti-bLF IgA and IgM were determined by enzyme-immuno assay; the percentages of IgA+ and IgM+ plasma cells (PC) and cytokine-producing CD4+ T cells of PP and LP were analyzed by flow cytometry. We found that total and bLf-specific IgA and IgM levels were increased in the intestinal secretions of the bLf group in comparison to mock group and day 0. LP IgA+ PC and IgM+ PC presented an initial elevation on day 7 and day 21, respectively, followed by a decrease on day 28 in comparison to mock. Higher percentages of CD4+ T cells in LP were found in the bLf group. Cytokines-producing CD4+ T cells populations presented a pattern of increases and decreases in the bLf group in both LP and PP. Transforming growth factor beta (TGF-β)+ CD4+ T cells showed higher percentages after bLf administration with a marked peak at day 21 in both LP and PP in comparison to mock-treated mice. Oral bLf exhibits complex immune properties in the proximal small intestine, where temporal monitoring of the inductor and effector compartments reveals patterns of rises and falls of different cell populations. Exceptionally, TGF-β+ CD4+ T cells show consistent higher numbers after bLf intervention across time. Our work suggests that isolated measurements do not show the complete picture of the modulatory effects of oral bLf in immunological sites as dynamic as the proximal small intestine.

scholarly journals Foxp3-Positive Regulatory T Cells Contribute to Antifibrotic Effects in Renal Fibrosis via an Interleukin-18 Receptor Signaling Pathway

2020 ◽  
Vol 7 ◽  
Author(s):  
Yasuaki Hirooka ◽  
Yuji Nozaki ◽  
Kaoru Niki ◽  
Asuka Inoue ◽  
Masafumi Sugiyama ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Cd4 T Cells ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Renal Diseases ◽  
Renal Interstitial Fibrosis

Renal interstitial fibrosis is a common lesion in the process of various progressive renal diseases. Interleukin (IL)-18 is a proinflammatory cytokine that plays an important role in the induction of Th1 responses and is associated with renal interstitial fibrosis, but the mechanism of fibrosis remains unclear. Here we used IL-18 receptor alpha knockout (IL-18Rα KO) mice to investigate the role of an IL-18Rα signaling pathway in renal fibrosis in a murine model of unilateral ureteral obstruction. IL-18 Rα KO mice showed decreased renal interstitial fibrosis and increased infiltration of CD4+ T cells and Foxp3+ regulatory T cells (Tregs) compared to wildtype (WT) mice. The expression of renal transforming growth factor beta 1 (TGF-β1, which is considered an important cytokine in renal interstitial fibrosis) was not significantly different between WT and IL-18Rα KO mice. The adoptive transfer of CD4+ T cells from the splenocytes of IL-18Rα KO mice to WT mice reduced renal interstitial fibrosis and increased the number of Foxp3+ Tregs in WT mice. These results demonstrated that Foxp3+ Tregs have a protective effect in renal interstitial fibrosis via an IL-18R signaling pathway.

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.

scholarly journals Ovalbumin-Derived Peptides Activate Retinoic Acid Signalling Pathways and Induce Regulatory Responses Through Toll-Like Receptor Interactions

Nutrients ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 831
Author(s):  
Mónica Martínez-Blanco ◽  
Leticia Pérez-Rodríguez ◽  
Daniel Lozano-Ojalvo ◽  
Elena Molina ◽  
Rosina López-Fandiño
Keyword(s):  
T Cells ◽  
Retinoic Acid ◽  
Aldehyde Dehydrogenase ◽  
Transforming Growth Factor Beta ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Foxp3 Expression ◽  
Interleukin 10 ◽  
Toll Like Receptor ◽  
Th2 Cytokine

This study investigates the potential of a hydrolysate of ovalbumin with pepsin (OP) to preclude Th2-type immunity by the enhancement of tolerogenic dendritic cells (DCs) and regulatory T (Treg) cells. Through Toll-like receptor (TLR) stimulation, OP enhances the retinoic acid pathway on DCs by means of the induction of aldehyde dehydrogenase enzymes and transforming growth factor beta (TGF-β), and it confers upon DC the ability to upregulate interleukin 10 (IL-10) as well as other tolerance-promoting mediators downstream of TRL signalling, such as IL-27, IL-33, Notch ligands, OX40L, and the transcription factors IRF4 and IRF8. OP-conditioned DCs induce the expansion of Foxp3+ and Tr1 cells in co-culture with CD4+ T cells. Furthermore, OP directly conditions CD4+ T cells from naïve mice, without the mediation of DCs, to express aldehyde dehydrogenase (ALDH) enzymes and, in the presence of the Th2 cytokine IL-4 and exogenous TGF-β, it enhances Foxp3 expression. It is noteworthy that, on CD4+ T cells isolated from egg-allergic mice, OP significantly enriches the levels of Foxp3+ and Foxp3+ RORγt+ CD4+ T cells. In conclusion, we show that food peptides may work, analogously to microbial-driven signals, through TLRs, to promote a tolerogenic phenotype on cells of the innate and adaptive immune system, a property that is further enhanced in the context of a Th2 cytokine-rich environment.

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