scholarly journals Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells

2010 ◽  
Vol 207 (7) ◽  
pp. 1381-1391 ◽  
Author(s):  
Yohsuke Harada ◽  
Yasuyo Harada ◽  
Chris Elly ◽  
Ge Ying ◽  
Ji-Hye Paik ◽  
...  
Keyword(s):  
T Cells ◽  
Ring Finger ◽  
Foxp3 Expression ◽  
Proximal Region ◽  
Binding Motif ◽  
Mechanistic Insight ◽  
T Cell Regulation ◽  
And Function ◽  
Deficient Mice ◽  
Insight Into

The transcription factor Foxp3 is essential for optimal regulatory T (T reg) cell development and function. Here, we show that CD4+ T cells from Cbl-b RING finger mutant knockin or Cbl-b–deficient mice show impaired TGF-β–induced Foxp3 expression. These T cells display augmented Foxo3a phosphorylation, but normal TGF-β signaling. Expression of Foxo3a rescues Foxp3 expression in Cbl-b–deficient T cells, and Foxo3a deficiency results in defective TGF-β–driven Foxp3 induction. A Foxo3a-binding motif is present in a proximal region of the Foxp3 promoter, and is required for Foxo3a association. Foxo1 exerts similar effects as Foxo3a on Foxp3 expression. This study reveals that Foxo factors promote transcription of the Foxp3 gene in induced T reg cells, and thus provides new mechanistic insight into Foxo-mediated T cell regulation.

scholarly journals CD1d-Independent NKT Cells in β2-Microglobulin-Deficient Mice Have Hybrid Phenotype and Function of NK and T Cells

2004 ◽  
Vol 172 (10) ◽  
pp. 6115-6122 ◽  
Author(s):  
Motoi Maeda ◽  
Ashleen Shadeo ◽  
Anna M. MacFadyen ◽  
Fumio Takei
Keyword(s):  
T Cells ◽  
Nkt Cells ◽  
Β2 Microglobulin ◽  
And Function ◽  
Deficient Mice

CD4+ Foxp3+ regulatory T cell-mediated immunomodulation by anti-depressants inhibiting acid sphingomyelinase

2018 ◽  
Vol 399 (10) ◽  
pp. 1175-1182 ◽  
Author(s):  
Jürgen Schneider-Schaulies ◽  
Niklas Beyersdorf
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cells ◽  
Tricyclic Antidepressant ◽  
Acid Sphingomyelinase ◽  
Human T Cells ◽  
And Function ◽  
Rate Limiting ◽  
Deficient Mice

AbstractAcid sphingomyelinase (ASM) is the rate-limiting enzyme cleaving sphingomyelin into ceramide and phosphorylcholin. CD4+Foxp3+regulatory T (Treg) cells depend on CD28 signaling for their survival and function, a receptor that activates the ASM. Both, basal and CD28-induced ASM activities are higher in Treg cells than in conventional CD4+T (Tconv) cells. In ASM-deficient (Smpd1−/−) as compared to wt mice, membranes of T cells contain 7–10-fold more sphingomyelin and two- to three-fold more ceramide, and are in a state of higher order than membranes of T cells from wt mice, which may facilitate their activation. Indeed, the frequency of Treg cells among CD4+T cells in ASM-deficient mice and their suppressive activityin vitroare increased. Moreover,in vitrostimulation of ASM-deficient T cells in the presence of TGF-β and IL-2 leads to higher numbers of induced Treg cells. Pharmacological inhibition of the ASM with a clinically used tricyclic antidepressant such as amitriptyline in mice or in tissue culture of murine or human T cells induces higher frequencies of Treg cells among CD4+T cells within a few days. This fast alteration of the balance between T cell populationsin vitrois due to the elevated cell death of Tconv cells and protection of the CD25highTreg cells by IL-2. Together, these findings suggest that ASM-inhibiting antidepressants, including a fraction of the serotonin re-uptake inhibitors (SSRIs), are moderately immunosuppressive and should be considered for the therapy of inflammatory and autoimmune disorders.

scholarly journals Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells

2015 ◽  
Vol 26 (15) ◽  
pp. 2845-2857 ◽  
Author(s):  
Magdalena Walecki ◽  
Florian Eisel ◽  
Jörg Klug ◽  
Nelli Baal ◽  
Agnieszka Paradowska-Dogan ◽  
...  
Keyword(s):  
T Cells ◽  
Androgen Receptor ◽  
Treg Cell ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Strong Increase ◽  
Histone H4 ◽  
And Function

CD4+CD25+Foxp3+ regulatory T (Treg) cells are able to inhibit proliferation and cytokine production in effector T-cells and play a major role in immune responses and prevention of autoimmune disease. A master regulator of Treg cell development and function is the transcription factor Foxp3. Several cytokines, such as TGF-β and IL-2, are known to regulate Foxp3 expression as well as methylation of the Foxp3 locus. We demonstrated previously that testosterone treatment induces a strong increase in the Treg cell population both in vivo and in vitro. Therefore we sought to investigate the direct effect of androgens on expression and regulation of Foxp3. We show a significant androgen-dependent increase of Foxp3 expression in human T-cells from women in the ovulatory phase of the menstrual cycle but not from men and identify a functional androgen response element within the Foxp3 locus. Binding of androgen receptor leads to changes in the acetylation status of histone H4, whereas methylation of defined CpG regions in the Foxp3 gene is unaffected. Our results provide novel evidence for a modulatory role of androgens in the differentiation of Treg cells.

scholarly journals Aberrant Contraction of Antigen-Specific CD4 T Cells after Infection in the Absence of Gamma Interferon or Its Receptor

2006 ◽  
Vol 74 (11) ◽  
pp. 6252-6263 ◽  
Author(s):  
Jodie S. Haring ◽  
John T. Harty
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Gamma Interferon ◽  
Model Systems ◽  
Important Regulator ◽  
Ifn Γ ◽  
And Function ◽  
Deficient Mice

ABSTRACT Several lines of evidence from different model systems suggest that gamma interferon (IFN-γ) is an important regulator of T-cell contraction after antigen (Ag)-driven expansion. To specifically investigate the role of IFN-γ in regulating the contraction of Ag-specific CD4 T cells, we infected IFN-γ−/− and IFN-γR1−/− mice with attenuated Listeria monocytogenes and monitored the numbers of Ag-specific CD4 T cells during the expansion, contraction, and memory phases of the immune response to infection. In the absence of IFN-γ or the ligand-binding portion of its receptor, Ag-specific CD4 T cells exhibited normal expansion in numbers, but in both strains of deficient mice there was very little decrease in the number of Ag-specific CD4 T cells even at time points later than day 90 after infection. This significant delay in contraction was not due to prolonged infection, since mice treated with antibiotics to conclusively eliminate infection exhibited the same defect in contraction. In addition to altering the number of Ag-specific CD4 T cells, the absence of IFN-γ signaling also changed the phenotype of cells generated after infection. IFN-γR1−/− Ag-specific CD4 T cells reacquired expression of CD127 more quickly than wild-type cells, and more IFN-γR1−/− CD4 T cells were capable of producing both IFN-γ and interleukin 2 following Ag stimulation. From these data we conclude that IFN-γ regulates the contraction, phenotype, and function of Ag-specific CD4 T cells generated after infection.

scholarly journals Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2–P2X7 pathway

2010 ◽  
Vol 207 (12) ◽  
pp. 2561-2568 ◽  
Author(s):  
Sandra Hubert ◽  
Björn Rissiek ◽  
Katjana Klages ◽  
Jochen Huehn ◽  
Tim Sparwasser ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Damage ◽  
Mouse Tumor ◽  
Single Domain Antibody ◽  
Cell Compartment ◽  
Selective Depletion ◽  
New Strategy ◽  
And Function ◽  
Deficient Mice

CD4+CD25+FoxP3+ regulatory T cells (T reg cells) play a major role in the control of immune responses but the factors controlling their homeostasis and function remain poorly characterized. Nicotinamide adenine dinucleotide (NAD+) released during cell damage or inflammation results in ART2.2–mediated ADP-ribosylation of the cytolytic P2X7 receptor on T cells. We show that T reg cells express the ART2.2 enzyme and high levels of P2X7 and that T reg cells can be depleted by intravenous injection of NAD+. Moreover, lower T reg cell numbers are found in mice deficient for the NAD-hydrolase CD38 than in wild-type, P2X7-deficient, or ART2-deficient mice, indicating a role for extracellular NAD+ in T reg cell homeostasis. Even routine cell preparation leads to release of NAD+ in sufficient quantities to profoundly affect T reg cell viability, phenotype, and function. We demonstrate that T reg cells can be protected from the deleterious effects of NAD+ by an inhibitory ART2.2-specific single domain antibody. Furthermore, selective depletion of T reg cells by systemic administration of NAD+ can be used to promote an antitumor response in several mouse tumor models. Collectively, our data demonstrate that NAD+ influences survival, phenotype, and function of T reg cells and provide proof of principle that acting on the ART2–P2X7 pathway represents a new strategy to manipulate T reg cells in vivo.

scholarly journals S06A1 Mechanistic insight into RNA acetylation to maintain the decoding fidelity in bacteria(Structural Biology of ncRNA Processing and Function)

2007 ◽  
Vol 47 (supplement) ◽  
pp. S8
Author(s):  
Sarin Chimnaronk ◽  
Tateki Suzuki ◽  
Tetsuhiro Manita ◽  
Yoshiho Ikeuchi ◽  
Min Yao ◽  
...  
Keyword(s):  
Structural Biology ◽  
Mechanistic Insight ◽  
And Function ◽  
Insight Into ◽  
Decoding Fidelity

Structural and mechanistic insight into alkane hydroxylation by Pseudomonas putida AlkB

2014 ◽  
Vol 460 (2) ◽  
pp. 283-293 ◽  
Author(s):  
Hernan Alonso ◽  
Oded Kleifeld ◽  
Adva Yeheskel ◽  
Poh C. Ong ◽  
Yu C. Liu ◽  
...  
Keyword(s):  
Ab Initio ◽  
Pseudomonas Putida ◽  
Structure And Function ◽  
Alkane Hydroxylation ◽  
Mechanistic Insight ◽  
Unknown Structure ◽  
And Function ◽  
Alkane Hydroxylases ◽  
Insight Into

Integral membrane non-haem di-iron alkane hydroxylases (AlkBs) are enzymes of unknown structure that allow bacteria to grow on alkanes. Catalysis-linked modifications with the inhibitor 1-octyne, mutagenesis studies and ab initio modelling provided novel insights into the structure and function of AlkB.

scholarly journals Jagged-1 regulates Foxp3 expression and cytokine production in CD4+ T cells

2019 ◽  
Author(s):  
Soichiro Kimura ◽  
Ronald Allen ◽  
Melissa Scola ◽  
Nicholas W Lukacs ◽  
Steven L. Kunkel ◽  
...  
Keyword(s):  
T Cells ◽  
Cytokine Production ◽  
Foxp3 Expression ◽  
Bacille Calmette Guerin ◽  
Altered Expression ◽  
Effector Cells ◽  
T Cell Regulation ◽  
Notch Ligands ◽  
Draining Lymph Nodes

AbstractNotch ligands are present during the interactions between T cells and dendritic cells (DC) and induce a myriad of effects that facilitate the activation of T cells, including the induction of T cell regulation, survival, and cytokine production. Although the ligands Delta-like 4 and Delta-like 1 are expressed as a function of DC activation, the notch ligand Jagged-1 is constitutively expressed on DC. We sought to determine the role of Jagged-1 in the interactions between CD4+ T cells and DC. We observed that Jagged-1 regulates Foxp3 expression, and Cd11cCre+Jaggedff mice have an altered expression of Foxp3 in effector cells that arise as a result of infection with the mycobacterium Bacille Calmette-Guerin. The observed changes in Foxp3 expression were correlated with an increase in cytokine production from cultures of antigen-stimulated draining lymph nodes.

scholarly journals A nanobody-based molecular toolkit provides new mechanistic insight into clathrin-coat initiation

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Linton M Traub
Keyword(s):  
Decisive Role ◽  
Subcellular Location ◽  
Combined Approach ◽  
Mechanistic Insight ◽  
Early Endosomes ◽  
The Stability ◽  
And Function ◽  
Insight Into ◽  
Complementarity Determining Region

Besides AP-2 and clathrin triskelia, clathrin coat inception depends on a group of early-arriving proteins including Fcho1/2 and Eps15/R. Using genome-edited cells, we described the role of the unstructured Fcho linker in stable AP-2 membrane deposition. Here, expanding this strategy in combination with a new set of llama nanobodies against EPS15 shows an FCHO1/2–EPS15/R partnership plays a decisive role in coat initiation. A nanobody containing an Asn-Pro-Phe peptide within the complementarity-determining region 3 loop is a function-blocking pseudoligand for tandem EPS15/R EH domains. Yet, in living cells, EH domains gathered at clathrin-coated structures are poorly accessible, indicating residence by endogenous NPF-bearing partners. Forcibly sequestering cytosolic EPS15 in genome-edited cells with nanobodies tethered to early endosomes or mitochondria changes the subcellular location and availability of EPS15. This combined approach has strong effects on clathrin coat structure and function by dictating the stability of AP-2 assemblies at the plasma membrane.

scholarly journals Human Bone Marrow Derived Mesenchymal Stromal Cells Enhance the Number and Function of Umbilical Cord Blood Peripheral Tregs during IL-2 Driven Ex Vivo Expansion

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1116-1116
Author(s):  
Jeong-Su Do ◽  
Alex Y. Huang ◽  
Daniel Zwick ◽  
Fei Zhong ◽  
David Askew ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Ex Vivo ◽  
Foxp3 Expression ◽  
Ex Vivo Expansion ◽  
Mitochondrial Transfer ◽  
And Function

Abstract Tumor growth factor β (TGF-β)-induced peripheral regulatory T cells (pTreg) are a promising therapeutic cell source that exhibit Foxp3 expression and suppressive functions similar to natural regulatory T cells. Nonetheless, their clinical potential is limited by the instability of Foxp3 expression and T cell exhaustion that occurs during ex vivo expansion. We postulated that mesenchymal stromal cells (MSCs) could enhance the number, function and Foxp3 expression stability of pTregs during IL-2 driven 21 day expansion due to their diverse immunomodulatory properties. In this study, we observed that use of a human bone marrow mesenchymal stromal cells (hBM-MSC) platform significantly enhanced the number of pTreg during IL-2 driven 21 day ex vivo expansion vs. standard suspension culture condition (MSC platform: 80.2 x 106 vs. IL2/media: 39.3 x 106, n=6; p<0.01). Also the number of pTreg expressing a naive phenotype (CD4+CD45RA+ and CD4+CD62L+ ) were significantly increased (CD45RA+; MSC platform: 74.4 ± 1.6 x 106 vs. IL2/media: 45.9 ± 2.9 x 106, n=6, p<0.001; CD62L+; MSC platform: 79.1 ± 1.3 x 106 vs. IL2/media: 54.5 ± 2.1 x 106, n=6, p<0.001), as well as stability of Foxp3 expression (IL-2/media: 88.2 ± 1.7% vs. MSC platform: 96.2 ± 1.1%, n=7; p<0.05). In addition, pTreg suppressive function was noted to be more potent during 21 day IL-2 driven ex vivo expansion compared to standard IL-2/media culture condition (MSC platform: 79% vs. media: 35% inhibition of T cell proliferation in 10:1 ratio, n=6; p<0.01). pTreg expanded over a hBM-MSC platform exhibited higher surface CD25, CTLA-4, and ICOS MFI expression (CD25; MSC platform: 1410 vs. Media: 774; p<0.001, CTLA-4; MSC platform: 1084 vs. Media: 318; p<0.001, ICOS; MSC platform: 4386 vs. Media: 2641, p<0.01, n=6). Notably, hBM-MSC enhancement of pTreg ex vivo expansion requires direct cell-cell contact, as Foxp3 expression in pTreg was not enhanced by hBM-MSC conditioned media (CM:73.4 ± 6.8% vs. MSC platform: 96.2 ± 1.0%, p<0.001; and IL2/media: 88.8 ± 1.6% vs. MSC platform: 96.2 ± 1.0%, p<0.01) nor in a trans-well culture experiments (Transwell: 83.4 ± 2.5% vs. IL2/media: 88.8 ± 1.6%; and Transwell: 83.4 ± 2.5% vs. MSC platform: 96.2 ± 1.0%, p<0.01). Importantly, optical sectioning microscopy and flow cytometry revealed that hBM-MSC supports Treg number and function via direct contact-dependent mitochondrial transfer (Figure 1A-B). Cytochalasin B treatment blocked mitochondrial transfer, suggesting that tunneling nanotubes (TNT) facilitate mitochondrial transfer from hBM-MSC to pTreg during IL-2 driven ex vivo expansion (Mock: 2208 ± 122.1 vs. Cyto B: 923.8 ± 89 MFI, n=6, p<0.0001). Moreover, the quantity of ATP (n=6; p<0.01) mitochondrial potential of pTreg (MSC platform: 9010 ± 224.5 vs. media: 7316 ± 122.7 MFI, n=6; p<0.01) were significantly enhanced in pTreg during IL-2 driven ex vivo expansion over a hBM-MSC platform. Taken together, hBM-MSC significantly improves the number, maturation, and function of pTreg during 21 day IL-2 driven ex vivo expansion. We have identified one key mechanism of action of hBM-MSC underlying these favorable effects on pTreg during ex vivo expansion to be mitochondrial transfer via TNT. Notably, these studies identify a novel role of hBM-MSC to overcome current limitations in IL-2/media suspension culture conditions including T cell senescence, and loss of Foxp3 expression. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document