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

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.

Download Full-text

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

Journal of Experimental Medicine ◽

10.1084/jem.191.2.225 ◽

2000 ◽

Vol 191 (2) ◽

pp. 225-238 ◽

Cited By ~ 53

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.

Download Full-text

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

Journal of Experimental Medicine ◽

10.1084/jem.20011341 ◽

2001 ◽

Vol 195 (1) ◽

pp. 15-22 ◽

Cited By ~ 388

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.

Download Full-text

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

Infection and Immunity ◽

10.1128/iai.73.2.849-858.2005 ◽

2005 ◽

Vol 73 (2) ◽

pp. 849-858 ◽

Cited By ~ 17

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.

Download Full-text

The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1406259111 ◽

2014 ◽

Vol 111 (30) ◽

pp. 11115-11120 ◽

Cited By ~ 48

Author(s):

M. Giordano ◽

R. Roncagalli ◽

P. Bourdely ◽

L. Chasson ◽

M. Buferne ◽

...

Keyword(s):

T Cells ◽

Tumor Necrosis Factor ◽

Antitumor Activity ◽

Tumor Necrosis Factor Alpha ◽

Cd8 T Cells ◽

Tumor Necrosis ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

Download Full-text

Apolipoprotein A-I inhibits the production of interleukin-1β and tumor necrosis factor-α by blocking contact-mediated activation of monocytes by T lymphocytes

Blood ◽

10.1182/blood.v97.8.2381 ◽

2001 ◽

Vol 97 (8) ◽

pp. 2381-2389 ◽

Cited By ~ 242

Author(s):

Nevila Hyka ◽

Jean-Michel Dayer ◽

Christine Modoux ◽

Tadahiko Kohno ◽

Carl K. Edwards ◽

...

Keyword(s):

T Cells ◽

Tumor Necrosis Factor ◽

T Lymphocytes ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Interleukin 1Β ◽

Apolipoprotein A ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

Abstract Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), essential components in the pathogenesis of immunoinflammatory diseases, are strongly induced in monocytes by direct contact with stimulated T lymphocytes. This study demonstrates that adult human serum (HS) but not fetal calf or cord blood serum displays inhibitory activity toward the contact-mediated activation of monocytes by stimulated T cells, decreasing the production of both TNF-α and IL-1β. Fractionation of HS and N-terminal microsequencing as well as electroelution of material subjected to preparative electrophoresis revealed that apolipoprotein A-I (apo A-I), a “negative” acute-phase protein, was the inhibitory factor. Functional assays and flow cytometry analyses show that high-density lipoprotein (HDL)-associated apo A-I inhibits contact-mediated activation of monocytes by binding to stimulated T cells, thus inhibiting TNF-α and IL-1β production at both protein and messenger RNA levels. Furthermore, apo A-I inhibits monocyte inflammatory functions in peripheral blood mononuclear cells activated by either specific antigens or lectins without affecting cell proliferation. These results demonstrate a new anti-inflammatory activity of HDL-associated apo A-I that might have modulating functions in nonseptic conditions. Therefore, because HDL has been shown to bind and neutralize lipopolysaccharide, HDL appears to play an important part in modulating both acute and chronic inflammation. The novel anti-inflammatory function of apo A-I reported here might lead to new therapeutic approaches in inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and atherosclerosis.

Download Full-text

CD8+ T Cells Specific to Apoptosis-Associated Antigens Predict the Response to Tumor Necrosis Factor Inhibitor Therapy in Rheumatoid Arthritis

PLoS ONE ◽

10.1371/journal.pone.0128607 ◽

2015 ◽

Vol 10 (6) ◽

pp. e0128607 ◽

Cited By ~ 10

Author(s):

Alessandra Citro ◽

Rossana Scrivo ◽

Helene Martini ◽

Carmela Martire ◽

Paolo De Marzio ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Tumor Necrosis Factor ◽

Cd8 T Cells ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Inhibitor ◽

Inhibitor Therapy ◽

Factor Inhibitor ◽

Necrosis Factor

Download Full-text

Dysregulation of Membrane-Bound Tumor Necrosis Factor-α and Tumor Necrosis Factor Receptors on Mononuclear Cells in Human Immunodeficiency Virus Type 1 Infection: Low Percentage of p75-Tumor Necrosis Factor Receptor Positive Cells in Patients With Advanced Disease and High Viral Load

Blood ◽

10.1182/blood.v90.7.2670.2670_2670_2679 ◽

1997 ◽

Vol 90 (7) ◽

pp. 2670-2679

Author(s):

Kjetil Hestdal ◽

Pål Aukrust ◽

Fredrik Müller ◽

Egil Lien ◽

Vigdis Bjerkeli ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Mononuclear Cells ◽

Healthy Controls ◽

Aids Patients ◽

Tnf Α ◽

Membrane Bound ◽

Factor Α ◽

Hiv 1 ◽

Necrosis Factor

The correlation of persistent tumor necrosis factor-α (TNF-α) activation with disease progression in patients infected with human immunodeficiency virus type 1 (HIV-1), suggests a role for TNF-α in the pathogenesis of HIV-1 infection. In the present study, we examined by flow cytometry the expression of membrane-bound (m) components of the TNF system in 33 HIV-1–infected patients and 12 healthy controls. While peripheral blood mononuclear cells (PBMC) from asymptomatic and symptomatic non-acquired immune deficiency syndrome (AIDS) patients showed a significantly increased percentage of mTNF-α+ and mTNF receptor (TNFR)+ cells compared with controls, this was not found in the AIDS group. Compared with healthy controls, AIDS patients had a significantly decreased percentage of both monocytes and lymphocytes expressing p75-TNFR. PBMC from AIDS patients showed a higher p75-TNFR mRNA level and a higher spontaneous release of soluble p75-TNFR than healthy individuals, suggesting enhanced cell surface turnover of this TNFR. The low expression of TNFRs on both lymphocytes and monocytes in the AIDS group was associated with high numbers of HIV-1 RNA copies in plasma, low numbers of CD4+ lymphocytes, and high serum levels of soluble TNFRs. AIDS patients had a decreased percentage of CD8+ lymphocytes expressing TNFRs compared with healthy controls. In contrast, these patients, as well as symptomatic non-AIDS patients, had an increased percentage of TNF-α+ and TNFRs+ cells among remaining CD4+ lymphocytes. The pattern of abnormalities seen in AIDS patients suggests a role for persistent activation of the TNF system in the accelerated CD4+ lymphocyte destruction, the enhanced HIV-1 replication, and the markedly impaired antimicrobial defense in advanced HIV-1-related disease.

Download Full-text

Antigen-primed CD8+ T cells can mediate resistance, preventing allogeneic marrow engraftment in the simultaneous absence of perforin-, CD95L-, TNFR1-, and TRAIL-dependent killing

Blood ◽

10.1182/blood-2002-09-2859 ◽

2003 ◽

Vol 101 (10) ◽

pp. 3991-3999 ◽

Cited By ~ 29

Author(s):

Masanobu Komatsu ◽

Michele Mammolenti ◽

Monica Jones ◽

Roland Jurecic ◽

Thomas J. Sayers ◽

...

Keyword(s):

T Cells ◽

Tumor Necrosis Factor ◽

Cd8 T Cells ◽

Barrier Function ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Proliferative Potential ◽

Allogeneic Bone ◽

Effector Pathways ◽

Necrosis Factor

Abstract Engraftment failure following allogeneic bone marrow (BM) transplantation is of clinical concern particularly involving T-cell–depleted inoculum and transplantations for aplastic anemia. Immune resistance by lymphoid and natural killer (NK) populations with “barrier” function is well established. Major histocompatibility complex (MHC)–identical marrow allografts were examined to investigate effector pathways in non-NK–mediated resistance. Barrier function was examined in cytotoxic normal and deficient B6 (H-2b) recipients primed to donor minor histocompatibility antigen (MiHA) prior to BM transplantation. Host resistance was sensitively evaluated by colony-forming unit (CFU) assays to directly assess for donor progenitor cell (PC) and peripheral chimerism. B6 host CD8+ T cells but not CD4+ or NK1.1+ cells effected rejection of primitive (CFU-HPP [high-proliferative potential]) and lineage-committed (CFU-IL3/GM [interleukin 3/granulocyte macrophage]) allogeneic donor progenitors. To address complementation by the cytotoxic pathways existing in singly deficient (perforin or FasL) recipients, cytotoxically double (perforin plus FasL) deficient (cdd) recipients were used. Resistance in B6-cdd recipients was comparable to that of wild-type B6 recipients and was also dependent on CD8+ T cells. A “triple” cytotoxic deficient model, involving transplantation of TNFR1−/− (tumor necrosis factor receptor 1) progenitor grafts did not diminish the ability of B6-cdd recipients to reject allografts. Finally, injection of anti-TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) monoclonal antibody (mAb) in B6-cdd recipients also failed to inhibit rejection of TNFR1−/− marrow grafts. In total, these studies demonstrate that CD8+ host T cells can effectively resist MHC-matched MiHA-mismatched donor PCs via alternative effector pathway(s) independent of perforin-, FasL-, TNFR-1–, and TRAIL-dependent cytotoxicity. Therefore, inhibition of these effector pathways in sensitized recipients is unlikely to result in stem cell engraftment following PC allografts.

Download Full-text