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.

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.

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 Isolation of viable antigen-specific CD8+ T cells based on membrane-bound tumor necrosis factor (TNF)-α expression

2011 ◽  
Vol 369 (1-2) ◽  
pp. 33-41 ◽  
Author(s):  
Danielle Haney ◽  
Máire F. Quigley ◽  
Tedi E. Asher ◽  
David R. Ambrozak ◽  
Emma Gostick ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Necrosis Factor ◽  
Cd8 T Cells ◽  
Tumor Necrosis ◽  
Tnf Α ◽  
Membrane Bound ◽  
Necrosis Factor

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.

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 Neonatal Tumor Necrosis Factor α Promotes Diabetes in Nonobese Diabetic Mice by Cd154-Independent Antigen Presentation to Cd8+ T Cells

2000 ◽  
Vol 191 (2) ◽  
pp. 225-238 ◽  
Author(s):  
E. Allison Green ◽  
F. Susan Wong ◽  
Koji Eshima ◽  
Conchi Mora ◽  
Richard A. Flavell
Keyword(s):  
T Cells ◽  
Tumor Necrosis Factor ◽  
Cd8 T Cells ◽  
Tumor Necrosis ◽  
Diabetic Mice ◽  
Autoreactive T Cells ◽  
Nonobese Diabetic ◽  
Tnf Α ◽  
Nonobese Diabetic Mice ◽  
Necrosis Factor

Neonatal islet-specific expression of tumor necrosis factor (TNF)-α in nonobese diabetic mice promotes diabetes by provoking islet-infiltrating antigen-presenting cells to present islet peptides to autoreactive T cells. Here we show that TNF-α promotes autoaggression of both effector CD4+ and CD8+ T cells. Whereas CD8+ T cells are critical for diabetes progression, CD4+ T cells play a lesser role. TNF-α–mediated diabetes development was not dependent on CD154–CD40 signals or activated CD4+ T cells. Instead, it appears that TNF-α can promote cross-presentation of islet antigen to CD8+ T cells using a unique CD40–CD154-independent pathway. These data provide new insights into the mechanisms by which inflammatory stimuli can bypass CD154–CD40 immune regulatory signals and cause activation of autoreactive T cells.

Conversion of Alloantigen-Specific CD8+ T-Cell Anergy to T-Cell Priming through In Vivo Ligation of Glucocorticoid-Induced Tumor Necrosis Factor Receptor.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1315-1315
Author(s):  
Hawk Kim ◽  
Byungsuk Kwon ◽  
Juyang Kim ◽  
Woon S. Choi ◽  
Hye J. Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Receptor ◽  
Cd8 T Cell ◽  
T Cell Anergy ◽  
Cell Anergy ◽  
Necrosis Factor

Abstract In this study, we investigated the effect of an agonistic mAb (DTA-1) against glucocorticoid-induced tumor necrosis factor receptor (GITR) in a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-host disease (cGVHD). A single dose of DTA-1 inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis, typical symptoms of cGVHD. DTA-1-treated mice showed clinical and pathological signs of acute GVHD (aGVHD), such as lymphopenia, loss of body weight, increase of donor cell engraftment, and intestinal damage, indicating that DTA-1 shifted cGVHD towards aGVHD. The conversion of cGVHD to aGVHD occurred because DTA-1 prevented donor CD8+ T cells from being anergic. Functionally active donor CD8+ T cells produced high levels of IFN-γ and had an elevated CTL activity against host antigens. In in vitro MLR, anergic responder CD8+ T cells were generated and DTA-1 stimulated the activation of responder CD8+ T cells that were fated to be anergic. We further confirmed in vivo that donor CD8+ T cells, but not donor CD4+ T cells, are responsible for the DTA-1-mediated conversion of cGVHD to aGVHD in a CD4+CD25+ regulatory T cell-independent manner. These results indicate that donor CD8+ T-cell anergy is a restriction factor in the development of aGVHD and that GITR stimulation prevent CD8+ T-cell anergy by activating CD8+ T cells prone to anergy. In sum, our data suggest GITR as an important costimulatory molecule regulating cGVHD versus aGVHD and as a target for therapeutic intervention in a variety of related diseases.

scholarly journals Regulatory T Cell–Resistant CD8+ T Cells Induced by Glucocorticoid-Induced Tumor Necrosis Factor Receptor Signaling

2008 ◽  
Vol 68 (14) ◽  
pp. 5948-5954 ◽  
Author(s):  
Hiroyoshi Nishikawa ◽  
Takuma Kato ◽  
Michiko Hirayama ◽  
Yuki Orito ◽  
Eiichi Sato ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
Cd8 T Cells ◽  
Regulatory T Cell ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Receptor ◽  
Receptor Signaling ◽  
Necrosis Factor

scholarly journals Role of Tumor Necrosis Factor Receptors in Regulating CD8 T-Cell Responses during Acute Lymphocytic Choriomeningitis Virus Infection

2005 ◽  
Vol 79 (1) ◽  
pp. 202-213 ◽  
Author(s):  
M. Suresh ◽  
Anju Singh ◽  
Christopher Fischer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tumor Necrosis ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Memory Cd8 T Cells ◽  
Cell Responses ◽  
Necrosis Factor

ABSTRACT The role of tumor necrosis factor (TNF) in regulating various phases of the antiviral T-cell response is incompletely understood. Additionally, despite strong evidence ascribing a role for TNF in protecting against T-cell-dependent autoimmunity, the underlying mechanisms are still obscure. To address these issues, we have investigated the role of tumor necrosis factor receptors (TNFRs) I (p55R) and II (p75R) in regulating CD8 T-cell responses to lymphocytic choriomeningitis virus (LCMV) with wild-type, p55R-deficient (p55−/−), p75R-deficient (p75−/−), and p55R- and p75R-deficient (DKO) mice. Loss of p55R increased the number of memory CD8 T cells to only one of the two immunodominant epitopes, and p75R deficiency had a minimal impact on the T-cell response to LCMV. Strikingly, deficiency of both p55R and p75R had a more dramatic effect on the LCMV-specific CD8 T-cell response; in the DKO mice, as a sequel to enhanced expansion and a reduction in contraction of CD8 T cells, there was a substantial increase in the number of memory CD8 T cells (specific to the two immunodominant epitopes). While the majority of LCMV-specific memory CD8 T cells in wild-type mice were CD62Lhi CCR7hi (central memory), a major proportion of memory CD8 T cells in DKO mice were CD62Llo CCR7hi. TNFR deficiency did not affect the proliferative renewal of memory CD8 T cells. Taken together, these data suggested that TNFRs p55R and p75R have overlapping roles in downregulating CD8 T-cell responses and establishment of immune homeostasis during an acute viral infection.

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