Agonistic antibodies to human glucocorticoid-induced tumor necrosis factor receptor as potential stimulators of T cell immunity for the treatment of cancer and viral infections

CD30 is a member of the tumor necrosis factor superfamily and a surface marker for Hodgkin's disease. Normal activated T cells and several virally transformed T or B cell lines also show CD30 expression. The interaction of CD30 with its ligand induces cell death or proliferation, depending on the cell type. In this report we characterize the signals mediated by the intracellular domain of CD30 and show that, in combination with signal(s) transduced by the T cell receptor, the multimerization of CD30 cytoplasmic domain induces Fas(CD95)-independent cell death in T cell hybridomas. Deletion analysis shows that the COOH-terminal 66 amino acids of CD30 are required to induce cell death. Using the yeast two-hybrid system, we have identified that the same region of CD30 interacts with tumor necrosis factor receptor-associated factor (TRAF)1 and TRAF2. These results indicate that TRAF1 and/or TRAF2 play an important role in cell death in addition to their previously identified roles in cell proliferation.

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Opposing role of tumor necrosis factor receptor 1 signaling in T cell-mediated hepatitis and bacterial infection in mice

Hepatology ◽

10.1002/hep.28551 ◽

2016 ◽

Vol 64 (2) ◽

pp. 508-521 ◽

Cited By ~ 11

Author(s):

Raluca Wroblewski ◽

Marietta Armaka ◽

Vangelis Kondylis ◽

Manolis Pasparakis ◽

Henning Walczak ◽

...

Keyword(s):

T Cell ◽

Tumor Necrosis Factor ◽

Bacterial Infection ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Necrosis Factor

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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.

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Tumor Necrosis Factor Receptor p55-Deficient Mice Respond to Acute Yersinia enterocolitica Infection with Less Apoptosis and More Effective Host Resistance

Infection and Immunity ◽

10.1128/iai.68.3.1243-1251.2000 ◽

2000 ◽

Vol 68 (3) ◽

pp. 1243-1251 ◽

Cited By ~ 21

Author(s):

Yi-Xue Zhao ◽

Ginette Lajoie ◽

Hongwei Zhang ◽

Basil Chiu ◽

Ursula Payne ◽

...

Keyword(s):

T Cell ◽

Tumor Necrosis Factor ◽

Yersinia Enterocolitica ◽

Acute Phase ◽

Host Defense ◽

Bacterial Infections ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Interleukin 10 ◽

Necrosis Factor

ABSTRACT Tumor necrosis factor (TNF) has generally been regarded as a protective cytokine in host defense against bacterial infections. In the present study, we evaluated the role of TNF in the acute phase of infection by Yersinia enterocolitica by using mice rendered genetically deficient in TNF receptor p55 (TNFRp55−/−). Unexpectedly, TNFRp55−/− mice showed more effective resistance to the bacteria, reflected in enhanced bacterial clearance and less tissue damage, than did control C57BL/6 mice. C57BL/6 mice showed evidence of extensive apoptosis in the spleen accompanied by a selective decrease in the CD4+-T-cell population of splenocytes, whereas TNFRp55−/− mice were spared these changes. The splenocytes from TNFRp55−/− mice also maintained a robust gamma interferon IFN-γ response to mitogenic stimulation, while the comparable response in C57BL/6 mice was impaired. In addition, splenocytes harvested from infected mice demonstrated lower production of interleukin-10 IL-10 in TNFRp55−/− mice than in C57BL/6 mice. These findings suggest that Yersinia can induce TNFRp55-mediated apoptosis of splenocytes in the acute phase of the infection and that alteration of T-cell-generated cytokines can dramatically alter the early events in host defense against this pathogen.

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Targeting Mycobacterium tuberculosis Tumor Necrosis Factor Alpha-Downregulating Genes for the Development of Antituberculous Vaccines

mBio ◽

10.1128/mbio.01023-15 ◽

2016 ◽

Vol 7 (3) ◽

Cited By ~ 19

Author(s):

Aaron Olsen ◽

Yong Chen ◽

Qingzhou Ji ◽

Guofeng Zhu ◽

Aruna Dharshan De Silva ◽

...

Keyword(s):

T Cell ◽

Tumor Necrosis Factor ◽

Host Cell ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Necrosis Factor Alpha ◽

Cell Responses ◽

Cell Immunity ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACT Tumor necrosis factor alpha (TNF) plays a critical role in the control of Mycobacterium tuberculosis , in part by augmenting T cell responses through promoting macrophage phagolysosomal fusion (thereby optimizing CD4 + T cell immunity by enhancing antigen presentation) and apoptosis (a process that can lead to cross-priming of CD8 + T cells). M. tuberculosis can evade antituberculosis (anti-TB) immunity by inhibiting host cell TNF production via expression of specific mycobacterial components. We hypothesized that M. tuberculosis mutants with an increased capacity to induce host cell TNF production (TNF-enhancing mutants) and thus with enhanced immunogenicity can be useful for vaccine development. To identify mycobacterial genes that regulate host cell TNF production, we used a TNF reporter macrophage clone to screen an H37Rv M. tuberculosis cosmid library constructed in M. smegmatis . The screen has identified a set of TNF-downregulating mycobacterial genes that, when deleted in H37Rv, generate TNF-enhancing mutants. Analysis of mutants disrupted for a subset of TNF-downregulating genes, annotated to code for triacylglycerol synthases and fatty acyl-coenzyme A (acyl-CoA) synthetase, enzymes that concern lipid biosynthesis and metabolism, has revealed that these strains can promote macrophage phagolysosomal fusion and apoptosis better than wild-type (WT) bacilli. Immunization of mice with the TNF-enhancing M. tuberculosis mutants elicits CD4 + and CD8 + T cell responses that are superior to those engendered by WT H37Rv. The results suggest that TNF-upregulating M. tuberculosis genes can be targeted to enhance the immunogenicity of mycobacterial strains that can serve as the substrates for the development of novel anti-TB vaccines. IMPORTANCE One way to control tuberculosis (TB), which remains a major global public health burden, is by immunization with an effective vaccine. The efficacy of Mycobacterium bovis BCG, the only currently approved TB vaccine, is inconsistent. Tumor necrosis factor alpha (TNF) is a cytokine that plays an important role in controlling TB. M. tuberculosis , the causative agent of TB, can counter this TNF-based defense by decreasing host cell TNF production. This study identified M. tuberculosis genes that can mediate inhibition of TNF production by macrophage (an immune cell critical to the control of TB). We have knocked out a number of these genes to generate M. tuberculosis mutants that can enhance macrophage TNF production. Immunization with these mutants in mice triggered a T cell response stronger than that elicited by the parental bacillus. Since T cell immunity is pivotal in controlling M. tuberculosis , the TNF-enhancing mutants can be used to develop novel TB vaccines.

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Interference with CD4+CD25+ T-cell-mediated tolerance to experimental autoimmune thyroiditis by glucocorticoid-induced tumor necrosis factor receptor monoclonal antibody

Journal of Autoimmunity ◽

10.1016/j.jaut.2005.09.003 ◽

2006 ◽

Vol 26 (1) ◽

pp. 24-31 ◽

Cited By ~ 28

Author(s):

Gerald P. Morris ◽

Yi-chi M. Kong

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Tumor Necrosis Factor ◽

Autoimmune Thyroiditis ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Experimental Autoimmune Thyroiditis ◽

Necrosis Factor ◽

Receptor Monoclonal Antibody ◽

Experimental Autoimmune

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Regulatory T Cells Expressing Tumor Necrosis Factor Receptor Type 2 Play a Major Role in CD4+ T-Cell Impairment During Sepsis

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa225 ◽

2020 ◽

Vol 222 (7) ◽

pp. 1222-1234 ◽

Cited By ~ 1

Author(s):

Benjamin J Gaborit ◽

Antoine Roquilly ◽

Cédric Louvet ◽

Abderrahmane Sadek ◽

Benoit Tessoulin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Necrosis Factor ◽

Regulatory T Cells ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Cd4 T Cell ◽

Treg Subset ◽

Necrosis Factor

Abstract Sepsis causes inflammation-induced immunosuppression with lymphopenia and alterations of CD4+ T-cell functions that renders the host prone to secondary infections. Whether and how regulatory T cells (Treg) are involved in this postseptic immunosuppression is unknown. We observed in vivo that early activation of Treg during Staphylococcus aureus sepsis induces CD4+ T-cell impairment and increases susceptibility to secondary pneumonia. The tumor necrosis factor receptor 2 positive (TNFR2pos) Treg subset endorsed the majority of effector immunosuppressive functions, and TNRF2 was particularly associated with activation of genes involved in cell cycle and replication in Treg, probably explaining their maintenance. Blocking or deleting TNFR2 during sepsis decreased the susceptibility to secondary infection. In humans, our data paralleled those in mice; the expression of CTLA-4 was dramatically increased in TNFR2pos Treg after culture in vitro with S. aureus. Our findings describe in vivo mechanisms underlying sepsis-induced immunosuppression and identify TNFR2pos Treg as targets for therapeutic intervention.

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