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.

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 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 The Sufficient Immunoregulatory Effect of Autologous Bone Marrow-Derived Mesenchymal Stem Cell Transplantation on Regulatory T Cells in Patients with Refractory Rheumatoid Arthritis

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Mohsen Ghoryani ◽  
Zhaleh Shariati-Sarabi ◽  
Jalil Tavakkol-Afshari ◽  
Mojgan Mohammadi
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Marrow ◽  
T Cells ◽  
Regulatory T Cells ◽  
Transforming Growth Factor Beta ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Joint Involvement ◽  
Peripheral Blood Mononuclear ◽  
Mesenchymal Stem Cell Transplantation

Rheumatoid arthritis (RA) is an advanced autoimmune disease described by joint involvement. The special properties of mesenchymal stem cells (MSCs) introduced them as a potential therapeutic candidate for RA. In this study, a single dose of autologous MSCs isolated from bone marrow (autologous BM-MSCs, 1×106 per kg) was injected intravenously into 13 patients suffering from refractory RA who were followed up within 12 months after the intervention to evaluate immunological elements. Our results showed that the gene expression of forkhead box P3 (FOXP3) in peripheral blood mononuclear cells (PBMCs) considerably increased at month 12. We found a substantial increasing trend in the culture supernatant levels of IL-10 and transforming growth factor-beta 1 (TGF-β1) in PBMCs from the beginning of the intervention up to the end. Our data may reflect the sufficient immunoregulatory effect of autologous BM-MSCs on regulatory T cells in patients suffering from refractory RA.

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3249-3256 ◽  
Author(s):  
Laurence Weiss ◽  
Vladimira Donkova-Petrini ◽  
Laure Caccavelli ◽  
Michèle Balbo ◽  
Cédric Carbonneil ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Highly Active Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Cell Subset ◽  
Transforming Growth Factor Β ◽  
Interleukin 10

Abstract The present study demonstrates that CD4+CD25+ T cells, expanded in peripheral blood of HIV-infected patients receiving highly active antiretroviral therapy (HAART), exhibit phenotypic, molecular, and functional characteristics of regulatory T cells. The majority of peripheral CD4+CD25+ T cells from HIV-infected patients expressed a memory phenotype. They were found to constitutively express transcription factor forkhead box P3 (Foxp3) messengers. CD4+CD25+ T cells weakly proliferated to immobilized anti-CD3 monoclonal antibody (mAb) and addition of soluble anti-CD28 mAb significantly increased proliferation. In contrast to CD4+CD25– T cells, CD4+CD25+ T cells from HIV-infected patients did not proliferate in response to recall antigens and to p24 protein. The proliferative capacity of CD4 T cells to tuberculin, cytomegalovirus (CMV), and p24 significantly increased following depletion of CD4+CD25+ T cells. Furthermore, addition of increasing numbers of CD4+CD25+ T cells resulted in a dose-dependent inhibition of CD4+CD25– T-cell proliferation to tuberculin and p24. CD4+CD25+ T cells responded specifically to p24 antigen stimulation by expressing transforming growth factor β (TGF-β) and interleukin 10 (IL-10), thus indicating the presence of p24-specific CD4+ T cells among the CD4+CD25+ T-cell subset. Suppressive activity was not dependent on the secretion of TGF-β or IL-10. Taken together, our results suggest that persistence of HIV antigens might trigger the expansion of CD4+CD25+ regulatory T cells, which might induce a tolerance to HIV in vivo.

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