Disease relevance of TNFRSF9

• Strong cytotoxicity of memory-type CTLs to a 4-1BB ligand-expressing Epstein-Barr virus (EBV)-transformed B-cell line was almost completely abrogated by 4-1BB-Fc, a soluble form of 4-1BB, suggesting involvement of 4-1BB in cytolytic processes [1].
• Functional expression of 4-1BB (CD137) in the inflammatory tissue in Crohn's disease [2].
• In contrast, only few 4-1BB-expressing cells were found in inflamed tissue from ulcerative colitis (UC) patients and almost no positive cells were found in control intestinal tissue [2].
• The analysis of OX40/4-1BB expression in patients with newly recognized Graves' disease revealed a statistically significant increase in the percentage of CD134+ T cells (7% vs 1.4%, p <0.001) and CD137+ T cells (3.2% vs 0.8%, p <0.04) compared to the control group [3].
• Agonists of CD137 have been used widely and successfully to treat cancer in animal models, and recently, it has become evident that CD137 agonists can also be used to treat autoimmune disease [4].

High impact information on TNFRSF9

• Previous studies have shown that short-term administrations of agonistic monoclonal antibodies against CD137, another TNF-receptor family member, activate T cells and induce rejection of allografts and established tumors [5].
• We reported previously that established tumors in mice receiving an agonistic mAb to the T cell costimulatory molecule 4-1BB (CD137) regress due to enhanced tumor antigen-specific cytotoxic T lymphocyte responses [6].
• Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB [7].
• Melanoma cells transfected to express CD83 induce antitumor immunity that can be increased by also engaging CD137 [8].
• Compared with other activation-induced antigens, CD137 showed a superior performance based on a consistently low baseline expression and a rapid up-regulation following alloantigen stimulation [9].

Chemical compound and disease context of TNFRSF9

• Therefore, this associated hypoglycemia was presumed to be not caused by excess glucose consumption by the tumor, not by excess secretion of IRI by the tumor, but caused by the presence of high level of ILA related to the tumor [10].

Biological context of TNFRSF9

• Anti-4-1BB costimulation also promoted long-term survival of CD28(-) CTLs, which were sensitive to activation-induced cell death upon anti-CD3 stimulation [1].
• The 4-1BB was induced preferentially on the CB CD28(-)CD8(+) T cells when CD28 down-regulation was induced by interleukin 15 (IL-15) and IL-12 stimulation [1].
• No apparent intrinsic kinase activity is seen with 4-1BB, which suggests that 4-1BB-associated molecules may be involved in 4-1BB-mediated signal transduction [11].
• Lymphocyte morphology in cultures with ILA-expressing CHO cells was suggestive of apoptosis [12].
• Our study suggests that the 4-1BB signal regulates CD28 co-stimulation in the targeted subset cells to favor Th1 development and maintain long-term cell growth [13].

Anatomical context of TNFRSF9

• While we were investigating the expression of OX40 and 4-1BB on activated human T cells, we found that they colocalize [14].
• Modulation of cord blood CD8+ T-cell effector differentiation by TGF-beta1 and 4-1BB costimulation [15].
• In the studies described in this work, we report that another family member, the ligand for 4-1BB (CD137), is expressed on various human carcinoma cell lines, on cells of solid tumors derived from these cell lines, and cells obtained from human tumors [16].
• 4-1BB ligand (L) expressed on antigen presenting cells (APC) interacts with 4-1BB, expressed on activated T cells and this interaction costimulates T cells to secrete cytokines and to proliferate [2].
• 4-1BB expression was better sustained on in vitro activated lamina propria T cells from CD patients compared to controls [2].

Associations of TNFRSF9 with chemical compounds

• OX40 and 4-1BB are members of the tumor necrosis factor (TNF) family of costimulatory receptors whose signaling is important for differential immune responses mediated by CD4+ or CD8+ T cells [14].
• Flow cytometry on propidium iodide-stained cells showed a time-dependent increase in the number of hypodiploid apoptotic cells when lymphocytes were cultured on ILA-expressing CHO cells [12].
• The mutation of this cysteine residue exerted no effect on trimerization but increased the dissociation rate of AviTag-4-1BBL from 4-1BB [17].
• Here, we investigated the transcriptional machinery required for T cell receptor (TCR) activation-dependent induction of 4-1BB expression in CD3-CEM cells treated with phorbol myristate acetate and ionomycin [18].
• Thus, we tested whether the treatment with other DNA-damaging agents, such as doxorubicin, bleomycin, and gamma-irradiation, could induce 4-1BB expression [19].

Physical interactions of TNFRSF9

• Recent studies highlight the participation of 4-1BB and its ligand 4-1BBL in a more complex network of immune cell responses and suggest that intervening in the 4-1BB costimulatory pathway might have some potential as a therapeutic approach to immune disorders [20].

Regulatory relationships of TNFRSF9

• This indicates critical roles for IL-4 and IL-12 in regulating 4-1BB effects on TGF-beta1-mediated suppression [15].
• The memory-type CD28(+) CTLs induced by anti-4-1BB costimulation acquired a greatly enhanced content of granzyme B, a cytolytic mediator, and enhanced cytotoxic activity as compared with CD28(-) CTLs [1].
• Finally, agonistic anti-4-1BB antibody enhanced interferon-gamma (IFN-gamma) production and proliferation of lamina propria T cells from CD patients [2].
• Human 4-1BB regulates CD28 co-stimulation to promote Th1 cell responses [13].
• The enhanced induction of CD30 expression by alloantigen was not common to other inducible TNFR family members because anti-CD3 plus anti-CD28 mAbs were far more effective in inducing expression of 4-1BB and OX-40 [21].

Other interactions of TNFRSF9

• We investigated whether TGF-beta1 responses could be reversed by 4-1BB costimulation during in vitro differentiation of naive CD8+ T cells into effector CTL cells [15].
• Taken together, our data suggest that 4-1BB/4-1BBL interactions contribute to the persistence of gut inflammation in CD [2].
• Human 4-1BB (CD137), a member of the tumor necrosis factor receptor (TNFR) superfamily, costimulates T cell activation [11].
• In addition, 4-1BB cross-linking with TCR signal in Jurkat cells and overexpression of 4-1BB in 293 cells were able to induce activation of the nuclear factor-kappa B (NF-kappa B) [11].
• The heterodimer of OX40 and 4-1BB was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under nonreduced conditions and was associated with the tumor receptor-associated factor (TRAF) family proteins in a unique manner [14].

Analytical, diagnostic and therapeutic context of TNFRSF9

• In immunohistochemistry, we found 4-1BB expression on lamina propria (LP) cells in inflamed and to a lesser extend in non-inflamed gut tissue from CD patients. mRNA levels for 4-1BB were also elevated in intestinal CD tissue [2].
• CD137 (ILA, 4-1BB), a member of the tumor necrosis factor receptor family, and its ligand CD137-L were assayed by RT-PCR and immunocytochemistry in cultured human brain cells [22].
• Using Southern blot analysis and polymerase chain reaction, we localized the CD137 gene to chromosome 1p36 [23].
• The present study also implicates that modulating 4-1BB/4-1BBL costimulatory pathway may be an effective immunotherapy strategy to augment the host response [24].
• The localization of 4-1BB proteins on tumor infiltrating T cells was determined by direct immunofluorescence cytochemical staining and detected by confocal microscopy [24].

References