Abstract 1208: Deficiency of Interleukin-1 receptor antagonist in T cells promotes Aortic Valve Stenosis by releasing Tumor Necrosis Factor-α

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kikuo Isoda ◽  
Taizo Matsuki ◽  
Tomiharu Niida ◽  
Norio Ishigami ◽  
Harumi Kondo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
Aortic Valve ◽  
Receptor Antagonist ◽  
Tumor Necrosis ◽  
Valve Leaflet ◽  
Aortic Valve Leaflet ◽  
Tnf Α ◽  
Necrosis Factor

The cytokine interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease. Activity of this cytokine is modulated endogenously via IL-1 receptor antagonist (IL-1Ra). We have shown that IL-1Ra-deficient (IL-1Ra −/− ) mice develop degenerative aortic valve stenosis (AS) that is the most common valvular disease in Western countries. The objective of this study is to determine the mechanisms by which deficiency of IL-1Ra may promote AS. Method and Results : IL-1Ra −/− mice (backcrossed 8 generations to the BALB/c background) and wild-type (WT) mice did not differ with regard to body weight, heart weight, and systolic arterial pressure. Furthermore, no significant differences in plasma lipid levels were observed between IL-1Ra −/− and WT mice. However histological analysis revealed that IL-1Ra −/− mice developed aortitis and showed increased aortic valve leaflet thickness compared to WT mice at the age of 12 weeks (p<0.001). Echo cardiograms also revealed that IL-1Ra −/− mice displayed higher transvalvular velocities than WT mice at the age of 40 weeks (p<0.01). These findings showed that IL-1Ra−/− mice spontaneously developed AS. In this study, we examined the role of T cells in development of AS by peripheral T cell transplantation. Transplantation of T cells from WT mice induced mild swelling of aortic valve leaflet in nu/nu mice. In contrast, T cells from IL-1Ra −/− mice induced an increase in aortic valve thickness in nu/nu mice. We next checked T cell function. After anti-CD3 antibody stimulation, IL-1Ra −/− T cells produced much higher levels of tumor necrosis factor (TNF)-α in culture supernatants compared to those from WT mice (p<0.001). Furthermore, in IL-1Ra −/− mice, TNF-α protein levels were higher than in WT mice (106.2±12.5 vs. 216.5±12.5 pg/mL, p<0.001) in vivo. Finally, we studied the roles of TNF-α in the development of AS in IL-1Ra −/− mice by generating double gene deficient (TNF-α −/− / IL-1Ra −/− ) mice. Interestingly, TNF-α −/− /IL-1Ra −/− mice did not develop AS. Conclusions : These findings suggest that IL-1Ra deficiency in T cells disrupts homeostasis of the immune system and TNF-α plays an important role in the development of AS in IL-1Ra −/− mice. These novel findings provide a clue for the development of new therapies for AS.

scholarly journals Repetitive Injections of Dendritic Cells Matured with Tumor Necrosis Factor α Induce Antigen-specific Protection of Mice from Autoimmunity

2001 ◽  
Vol 195 (1) ◽  
pp. 15-22 ◽  
Author(s):  
Mauritius Menges ◽  
Susanne Rößner ◽  
Constanze Voigtländer ◽  
Heike Schindler ◽  
Nicole A. Kukutsch ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Cell Immunity ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Mature dendritic cells (DCs) are believed to induce T cell immunity, whereas immature DCs induce T cell tolerance. Here we describe that injections of DCs matured with tumor necrosis factor (TNF)-α (TNF/DCs) induce antigen-specific protection from experimental autoimmune encephalomyelitis (EAE) in mice. Maturation by TNF-α induced high levels of major histocompatibility complex class II and costimulatory molecules on DCs, but they remained weak producers of proinflammatory cytokines. One injection of such TNF/DCs pulsed with auto-antigenic peptide ameliorated the disease score of EAE. This could not be observed with immature DCs or DCs matured with lipopolysaccharide (LPS) plus anti-CD40. Three consecutive injections of peptide-pulsed TNF/DCs derived from wild-type led to the induction of peptide-specific predominantly interleukin (IL)-10–producing CD4+ T cells and complete protection from EAE. Blocking of IL-10 in vivo could only partially restore the susceptibility to EAE, suggesting an important but not exclusive role of IL-10 for EAE prevention. Notably, the protection was peptide specific, as TNF/DCs pulsed with unrelated peptide could not prevent EAE. In conclusion, this study describes that stimulation by TNF-α results in incompletely matured DCs (semi-mature DCs) which induce peptide-specific IL-10–producing T cells in vivo and prevent EAE.

scholarly journals Tumor Necrosis Factor Receptor-1 (p55) Deficiency Attenuates Tumor Growth and Intratumoral Angiogenesis and Stimulates CD8+ T Cell Function in Melanoma

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2469
Author(s):  
Yamila I. Rodriguez ◽  
Ludmila E. Campos ◽  
Melina G. Castro ◽  
Nadia Bannoud ◽  
Ada G. Blidner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
Tumor Cell ◽  
Cd8 T Cells ◽  
Tumor Necrosis ◽  
Cd8 T Cell ◽  
Tnf Α ◽  
The Impact ◽  
Necrosis Factor

The role of tumor necrosis factor-α (TNF-α) in shaping the tumor microenvironment is ambiguous. Consistent with its uncertain role in melanoma, TNF-α plays a dual role, either acting as a cytotoxic cytokine or favoring a tumorigenic inflammatory microenvironment. TNF-α signals via two cognate receptors, namely TNFR1 (p55) and TNFR2 (p75), which mediate divergent biological activities. Here, we analyzed the impact of TNFR1 deficiency in tumor progression in the B16.F1 melanoma model. Tumors developed in mice lacking TNFR1 (TNFR1 knock-out; KO) were smaller and displayed lower proliferation compared to their wild type (WT) counterpart. Moreover, TNFR1 KO mice showed reduced tumor angiogenesis. Although no evidence of spontaneous metastases was observed, conditioned media obtained from TNFR1 KO tumors increased tumor cell migration. Whereas the analysis of tumor-associated immune cell infiltrates showed similar frequency of total and M2-polarized tumor-associated macrophages (TAMs), the percentage of CD8+ T cells was augmented in TNFR1 KO tumors. Indeed, functional ex vivo assays demonstrated that CD8+ T cells obtained from TNFR1KO mice displayed an increased cytotoxic function. Thus, lack of TNFR1 attenuates melanoma growth by modulating tumor cell proliferation, migration, angiogenesis and CD8+ T cell accumulation and activation, suggesting that interruption of TNF-TNFR1 signaling may contribute to control tumor burden.

Function of CD4+CD3− cells in relation to B- and T-zone stroma in spleen

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1602-1610 ◽  
Author(s):  
Mi-Yeon Kim ◽  
Fiona M. McConnell ◽  
Fabrina M. C. Gaspal ◽  
Andrea White ◽  
Stephanie H. Glanville ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
Stromal Cells ◽  
Tumor Necrosis ◽  
Accessory Cell ◽  
Segregation Process ◽  
Tnf Α ◽  
Deficient Mice ◽  
Necrosis Factor

Abstract Lymphocytes from lymphotoxin (LT) α–deficient mice, which lack segregation of their B- and T-cell areas, acquire normal organization following adoptive transfer into RAG-deficient recipients, identifying a non-B non-T cell in the segregation process. Here we show that a CD4+CD3− accessory cell is tightly associated with discrete VCAM-1–expressing stromal cells in B- and T-cell areas of the mouse spleen. CD4+CD3− cells express high levels of LTα, LTβ, and tumor necrosis factor (TNF) α, which are the ligands for the LTβ receptor and TNFR1 expressed by stromal cells. The expression of these ligands is functional, as transferring CD4+CD3− cells derived from either embryonic or adult tissues into LTα-deficient mice organizes B/T segregation and up-regulates CCL21 protein expression in areas where T cells are segregated from B cells. We propose that the function of CD4+CD3− cells is to form a link between primed CD4 T cells and the underlying stromal elements, creating distinct microenvironments in which they enable effector responses.

scholarly journals The TNF-α/TNFR2 Pathway: Targeting a Brake to Release the Anti-tumor Immune Response

2021 ◽  
Vol 9 ◽  
Author(s):  
Audrey Moatti ◽  
José L. Cohen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
Signaling Pathway ◽  
Immune Checkpoint ◽  
Tumor Necrosis ◽  
Tnf Α ◽  
Anti Cancer ◽  
Necrosis Factor

Newly discovered anti-cancer immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T cells, focus on spurring the anti-tumor effector T cell (Teff) response. Although such strategies have already demonstrated a sustained beneficial effect in certain malignancies, a substantial proportion of treated patients does not respond. CD4+FOXP3+ regulatory T cells (Tregs), a suppressive subset of T cells, can impair anti-tumor responses and reduce the efficacy of currently available immunotherapies. An alternative view that has emerged over the last decade proposes to tackle this immune brake by targeting the suppressive action of Tregs on the anti-tumoral response. It was recently demonstrated that the tumor necrosis factor alpha (TNF-α) tumor necrosis factor receptor 2 (TNFR2) is critical for the phenotypic stabilization and suppressive function of human and mouse Tregs. The broad non-specific effects of TNF-α infusion in patients initially led clinicians to abandon this signaling pathway as first-line therapy against neoplasms. Previously unrecognized, TNFR2 has emerged recently as a legitimate target for anti-cancer immune checkpoint therapy. Considering the accumulation of pre-clinical data on the role of TNFR2 and clinical reports of TNFR2+ Tregs and tumor cells in cancer patients, it is now clear that a TNFR2-centered approach could be a viable strategy, once again making the TNF-α pathway a promising anti-cancer target. Here, we review the role of the TNFR2 signaling pathway in tolerance and the equilibrium of T cell responses and its connections with oncogenesis. We analyze recent discoveries concerning the targeting of TNFR2 in cancer, as well as the advantages, limitations, and perspectives of such a strategy.

scholarly journals Prostaglandin E2 and Tumor Necrosis Factor α Cooperate to Activate Human Dendritic Cells: Synergistic Activation of Interleukin 12 Production

1997 ◽  
Vol 186 (9) ◽  
pp. 1603-1608 ◽  
Author(s):  
Claudia Rieser ◽  
Günther Böck ◽  
Helmut Klocker ◽  
Georg Bartsch ◽  
Martin Thurnher
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
Prostaglandin E2 ◽  
Tumor Necrosis ◽  
Interleukin 12 ◽  
Dependent Manner ◽  
Tnf Α ◽  
Human Dendritic Cells ◽  
Necrosis Factor

Interleukin (IL)-12 is a proinflammatory cytokine that contributes to innate resistance and to the development of antigen-specific T cell responses. Among other effects, prostaglandin E2 (PGE2) inhibits the production of IL-12 by macrophages activated with lipopolysaccharide (LPS). Here we investigated the effects of PGE2 on human dendritic cells (DCs) which develop in the presence of GM-CSF and IL-4. We demonstrate that in the absence of LPS, PGE2 dose dependently stimulated the production of IL-12 by DCs. Although PGE2 alone stimulated the production of low amounts of IL-12 only, it synergized with tumor necrosis factor (TNF)-α to induce high levels of IL-12 production by DCs. Addition of TNF-α in the absence of PGE2 had no effect on IL-12 production. Conversely, in the presence of LPS, PGE2 inhibited IL-12 production by DCs in a dose-dependent manner. The combination of PGE2 and TNF-α efficiently silenced mannose receptor–mediated endocytosis in DCs and readily induced neo-expression of the CD83 antigen. In addition, the expression of various surface antigens such as major histocompatibility complex class I and II, adhesion, as well as costimulatory molecules was upregulated by this treatment. The effects of PGE2 on IL-12 synthesis and CD83 expression could be mimicked by dibutyryl-cAMP and forskolin, indicating that they were due to the intracellular elevation of cAMP levels. DC treated with PGE2 and TNF-α were most potent in stimulating allogeneic T cell proliferation. Our data demonstrate that PGE2 contributes to the maturation of human DCs and that PGE2 can be a potent enhancer of IL-12 production by human DCs.

Alteration of tumor necrosis factor–α T-cell homeostasis following potent antiretroviral therapy: contribution to the development of human immunodeficiency virus–associated lipodystrophy syndrome

Blood ◽  
2000 ◽  
Vol 95 (10) ◽  
pp. 3191-3198 ◽  
Author(s):  
Eric Ledru ◽  
Névéna Christeff ◽  
Olivier Patey ◽  
Pierre de Truchis ◽  
Jean-Claude Melchior ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Interleukin 2 ◽  
Hiv Patients ◽  
Immunodeficiency Virus ◽  
Necrosis Factor

Abstract Highly-active antiretroviral therapy (HAART) has lead to a dramatic decrease in the morbidity of patients infected with the human immunodeficiency virus (HIV). However, metabolic side effects, including lipodystrophy-associated (LD-associated) dyslipidemia, have been reported in patients treated with antiretroviral therapy. This study was designed to determine whether successful HAART was responsible for a dysregulation in the homeostasis of tumor necrosis factor- (TNF-), a cytokine involved in lipid metabolism. Cytokine production was assessed at the single cell level by flow cytometry after a short-term stimulation of peripheral blood T cells from HIV-infected (HIV+) patients who were followed during 18 months of HAART. A dramatic polarization to TNF- synthesis of both CD4 and CD8 T cells was observed in all patients. Because it was previously shown that TNF- synthesis by T cells was highly controlled by apoptosis, concomitant synthesis of TNF- and priming for apoptosis were also analyzed. The accumulation of T cells primed for TNF- synthesis is related to their escape from activation-induced apoptosis, partly due to the cosynthesis of interleukin-2 (IL-2) and TNF-. Interestingly, we observed that LD is associated with a more dramatic TNF- dysregulation, and positive correlations were found between the absolute number of TNF- CD8 T-cell precursors and lipid parameters usually altered in LD including cholesterol, triglycerides, and the atherogenic ratio apolipoprotein B (apoB)/apoA1. Observations from the study indicate that HAART dysregulates homeostasis of TNF- synthesis and suggest that this proinflammatory response induced by efficient antiretroviral therapy is a risk factor of LD development in HIV+ patients.

scholarly journals Invariant Vα14 Chain NKT Cells Promote Plasmodium berghei Circumsporozoite Protein-Specific Gamma Interferon- and Tumor Necrosis Factor Alpha-Producing CD8+ T Cells in the Liver after Poxvirus Vaccination of Mice

2005 ◽  
Vol 73 (2) ◽  
pp. 849-858 ◽  
Author(s):  
Simone Korten ◽  
Richard J. Anderson ◽  
Carolyn M. Hannan ◽  
Eric G. Sheu ◽  
Robert Sinden ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Necrosis Factor ◽  
Plasmodium Berghei ◽  
Tumor Necrosis ◽  
Nkt Cells ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Necrosis Factor

ABSTRACT Understanding the protective mechanism in the liver induced by recombinant vaccines against the pre-erythrocytic stages of malaria is important for vaccine development. Most studies in mice have focused on splenic and peripheral blood T cells and identified gamma interferon (IFN-γ)-producing CD8+ T cells as correlates of protection, which can be induced by prime-boost vaccination with recombinant poxviruses. Invariant natural killer T (Vα14iNKT) cells can also protect against liver stage malaria, when activated, and are abundant in the liver. Since poxviruses have nonspecific immunomodulating effects, which are incompletely understood, we investigated whether recombinant poxviruses affect the protective properties of hepatic Vα14iNKT cells and thus vaccine efficacy. We show that intradermal vaccination with recombinant poxviruses activated Vα14iNKT cells and NK cells in the livers of BALB/c mice while inducing IFN-γ- and tumor necrosis factor alpha (TNF-α)-producing pre-erythrocytic stage antigen-specific CD8+ T cells. Greater numbers of hepatic Vα14iNKT cells secreted interleukin-4 than IFN-γ. Vaccinated Vα14iNKT-cell-deficient mice had lower, but still protective levels of hepatic and splenic IFN-γ+ and TNF-α+ CD8+ T cells and better protection rates later after challenge with Plasmodium berghei sporozoites. Therefore, vaccine-activated hepatic Vα14iNKT cells help in generating specific T cells but are not required for protection induced by recombinant poxviruses. Furthermore, double-positive INF-γ+/TNF-α+ CD8+ T cells were enriched in protected livers, suggesting that cells expressing both of these cytokines may be most relevant for protection.

scholarly journals TRANCE (Tumor Necrosis Factor [TNF]-related Activation-induced Cytokine), a New TNF Family Member Predominantly Expressed in T cells, Is a Dendritic Cell–specific Survival Factor

1997 ◽  
Vol 186 (12) ◽  
pp. 2075-2080 ◽  
Author(s):  
Brian R. Wong ◽  
Régis Josien ◽  
Soo Young Lee ◽  
Birthe Sauter ◽  
Hong-Li Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Dominant Negative ◽  
Mouse Bone Marrow ◽  
Survival Factor ◽  
Necrosis Factor

TRANCE (tumor necrosis factor [TNF]–related activation-induced cytokine) is a new member of the TNF family that is induced upon T cell receptor engagement and activates c-Jun N-terminal kinase (JNK) after interaction with its putative receptor (TRANCE-R). In addition, TRANCE expression is restricted to lymphoid organs and T cells. Here, we show that high levels of TRANCE-R are detected on mature dendritic cells (DCs) but not on freshly isolated B cells, T cells, or macrophages. Signaling by TRANCE-R appears to be dependent on TNF receptor–associated factor 2 (TRAF2), since JNK induction is impaired in cells from transgenic mice overexpressing a dominant negative TRAF2 protein. TRANCE inhibits apoptosis of mouse bone marrow–derived DCs and human monocyte-derived DCs in vitro. The resulting increase in DC survival is accompanied by a proportional increase in DC-mediated T cell proliferation in a mixed leukocyte reaction. TRANCE upregulates Bcl-xL expression, suggesting a potential mechanism for enhanced DC survival. TRANCE does not induce the proliferation of or increase the survival of T or B cells. Therefore, TRANCE is a new DC-restricted survival factor that mediates T cell–DC communication and may provide a tool to selectively enhance DC activity.

Generation of T cells from adult human hematopoietic stem cells and progenitors in a fetal thymic organ culture system: stimulation by tumor necrosis factor-α

Blood ◽  
2000 ◽  
Vol 95 (9) ◽  
pp. 2806-2812 ◽  
Author(s):  
Steven F. A. Weekx ◽  
Hans W. Snoeck ◽  
Fritz Offner ◽  
Magda De Smedt ◽  
Dirk R. Van Bockstaele ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
Organ Culture ◽  
Cell Survival ◽  
Tumor Necrosis ◽  
Hematopoietic Stem ◽  
Fetal Thymic Organ Culture ◽  
Necrosis Factor

To investigate the T-lymphopoietic capacity of human adult bone marrow (ABM) hematopoietic progenitor cells, CD34+Lin−, CD34+CD38+, and CD34++CD38− cells were cultured in a severe combined immunodeficient (SCID) mouse fetal thymic organ culture (FTOC). Direct seeding of these progenitors resulted in a moderate to severe cell loss, particularly for the CD34++CD38− cell fraction, and T cells could only be generated from the CD34+Lin− fraction. Preincubation for 36 hours with interleukin-3 (IL-3) and stem cell factor (SCF) led to an improved cell survival and proliferation, although T-cell development was seen only in the CD34+Lin− fraction. Addition of tumor necrosis factor (TNF)- to IL-3 + SCF-supplemented preincubation medium resulted in optimal cell survival, cell proliferation. and T-cell generation of all 3 cell fractions. The TNF- effect resulted in an up-regulation of CD127 (ie, the IL-7 receptor -chain) in a small subset of the CD34+ cells. No evidence could be generated to support the possibility that TNF- inhibits a cell population that suppresses T-cell differentiation. A quantitatively different T-cell generation potency was still seen between the 3 subpopulations: CD34+Lin− (100% success rate) &gt; CD34+CD38+ (66%) &gt; CD34++CD38− (25%). These data contrast with our previous findings using fetal liver and cord blood progenitors, which readily differentiate into T-lymphocytes in FTOC, even without prestimulation with cytokines. Our results demonstrate that adult CD34++CD38− cells, known to contain hematopoietic stem cells, can differentiate into T-lymphocytes and that a significant difference exists in T-lymphopoietic activity of stem cells derived from ontogenetically different sources.

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