Disease relevance of Tnfrsf9

• These results show that immunization with a single LCMV peptide provides long term protection against LCMV infection and point to costimulatory molecules such as 4-1BB as important components for generating protective immunity after vaccination [1].
• Up-regulation of 4-1BB was also observed by infection with Escherichia coli, Salmonella typhimurium, and Staphylococcus aureus, and by treatment with lipopolysaccharides and heat-killed BCG [2].
• Blocking 4-1BB/4-1BB ligand interactions prevents herpetic stromal keratitis [3].
• 4-1BB (CD137) differentially regulates murine in vivo protein- and polysaccharide-specific immunoglobulin isotype responses to Streptococcus pneumoniae [4].
• These data provide evidence in support of Idd9.3 as the locus encoding 4-1BB and suggest that the 4-1BB signaling pathway could have a primary function in the etiology of autoimmune disease [5].

High impact information on Tnfrsf9

• Monoclonal antibodies against the T-cell activation molecule 4-1BB have been effective in the treatment of established mouse tumors [6].
• Expression of 4-1BB is restricted to primed CD4+ and CD8+ T cells, and 4-1BB signaling either by binding to 4-1BBL or by antibody ligation delivers a dual mitogenic signal for T-cell activation and growth [7].
• The 4-1BB glycoprotein is a member of the tumor necrosis factor receptor superfamily and binds to a high-affinity ligand (4-1BBL) expressed on several antigen-presenting cells such as macrophages and activated B cells [7].
• Here we show that anti-mouse 4-1BB monoclonal antibodies (mAbs) inhibit thymus-dependent antibody production by B cells [8].
• The 4-1BB receptor is an inducible type I membrane protein and member of the tumor necrosis factor receptor (TNFR) superfamily that is rapidly expressed on the surface of CD4+ and CD8+ T cells after antigen- or mitogen-induced activation [9].

Chemical compound and disease context of Tnfrsf9

• In this study, we demonstrate that several poorly immunogenic tumors, including C3 tumor, TC-1 lung carcinoma, and B16-F10 melanoma, once established as solid tumors or metastases, are refractory to treatment by anti-4-1BB mAb [10].

Biological context of Tnfrsf9

• These data support the idea that CD28 plays a primary role in initial T cell expansion, whereas 4-1BB/4-1BBL sustains both CD4 and CD8 T cell responses, as well as enhances cell division and T cell effector function [11].
• Analysis of cell surface phenotypes showed that the failure to develop HSK in the 4-1BB(-/-) mice was associated with a reduced expression of CD62L at the time of T cell migration into the corneal stroma [3].
• The expression pattern of 4-1BB and 4-1BB ligand (4-1BBL) has suggested that 4-1BB plays a role not only in various responses related to innate immunity but also in bone metabolism [12].
• Our results suggest a role for cyclin D2, D3, and E, and p27(kip1) proteins in the 4-1BB-mediated cell cycle progression of CD8(+) T cells in vivo [13].
• Optimal 4-1BB expression was seen by day 6 post-stimulation and was cell density dependent [14].

Anatomical context of Tnfrsf9

• In correlation with their selective effects on humoral and cellular immune responses, these chemokines also differentially attract CD4(+) versus CD8(+) T cells and modulate CD40, CD80, and CD86 expressed by B220(+) cells as well as CD28, 4-1BB, and gp39 expression by CD4(+) and CD8(+) T cells in a dose-dependent fashion [15].
• Enhanced osteoclastogenesis was observed in bone marrow-derived macrophage cells from 4-1BB-deficient mice than in those from wildtype mice [12].
• When IL-10 was added to the culture medium, osteoclast formation was inhibited more efficiently in the 4-1BB(-/-) BMMs than in the wildtype BMMs [12].
• 4-1BB (CD137) is induced on activated CD4(+) and CD8(+) T cells and delivers a costimulatory signal upon binding the 4-1BB ligand (4-1BBL) expressed on antigen-presenting cells [4].
• Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells [16].

Associations of Tnfrsf9 with chemical compounds

• These data are the first to suggest a stimulatory role for endogenous 4-1BB-4-1BBL interactions during a humoral immune response to a pathogen and further underscore significant differences in costimulation requirements for an in vivo protein- versus polysaccharide-specific Ig isotype response to an extracellular bacterium [4].
• The interaction between extracellular matrix proteins and 4-1BB was completely blocked by the anionic carbohydrate polymer fucoidan and was partially blocked by the anionic carbohydrate polymer dextran sulfate and the glycosaminoglycan heparin sulfate but was unaffected by desulfated heparin [17].
• Optimal induction of 4-1BB mRNA in T cells required both PMA and ionomycin stimulation, indicating that protein kinase C activation and increases in intracellular Ca2+ were required for its expression [18].
• 4-1BB extracellular domain contains four potential C6 (CXn C XX C XX CXn C Xn C) motifs, of which the first motif is partial and the third is distinct from those of nerve growth factor receptor or TNF receptor 1 [19].
• 4-1BB was categorized as an early activation gene since the protein synthesis inhibitor, cycloheximide, blocked the induction of 4-1BB mRNA [18].

Physical interactions of Tnfrsf9

• 4-1BBL binds to 4-1BB (CD137) on activated CD4 and CD8 T cells and in conjunction with strong signals through the TCR provides a CD28-independent costimulatory signal leading to high level IL-2 production by primary resting T cells [20].

Regulatory relationships of Tnfrsf9

• The optimal effect of 4-1BBL in CTL stimulation required B7-CD28 interaction since blockade of this interaction by antibodies down-regulated the expression of 4-1BB on T cells and decreased CTL activity [21].
• The T cell costimulatory receptor 4-1BB enhances cell cycle progression and proliferation of CD8(+) T cells in both an IL-2-dependent and -independent manner [13].
• 4-1BB enhances CD8+ T cell expansion by regulating cell cycle progression through changes in expression of cyclins D and E and cyclin-dependent kinase inhibitor p27kip1 [13].
• Results: Expression of IL-10 was higher in RANKL-stimulated wildtype BMMs than 4-1BB(-/-) BMMs [12].
• 4-1BB-induced p38 MAPK activation is inhibited by the p38-specific inhibitor SB203580 in both a T cell hybridoma and in murine T cells [22].

Other interactions of Tnfrsf9

• Under the same conditions, CD8 T cells expressed 4-1BB, but no detectable OX40 [23].
• Introduction: 4-1BB is an inducible T-cell costimulatory molecule and a member of the TNF receptor family [12].
• Regulation of 4-1BB expression by cell-cell interactions and the cytokines, interleukin-2 and interleukin-4 [14].
• T cells activated with soluble anti-CD3 (anti-CD3s) in the presence of IL-2, IL-4, or accessory cells, did not express higher levels of 4-1BB on their cell surface [14].
• These data suggest that initial events crucial for efficient T cell activation, such as signals delivered through the T cell receptor/CD3 complex and the CD28 molecule, are instrumental in regulating subsequent 4-1BB expression [14].

Analytical, diagnostic and therapeutic context of Tnfrsf9

• 4-1BB costimulation is required for protective anti-viral immunity after peptide vaccination [1].
• In an adoptive transfer model, CD4 T cells expressed 4-1BB and OX40 sequentially in response to immunization, with little or no overlap in the timing of their expression [23].
• Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor [24].
• In contrast, anti-4-1BB MAb has no effect on the anti-PspA response when injected only at the time of secondary immunization [4].
• In adoptive immunotherapy, the coadministration of 4-1BB mAb enhanced the therapeutic efficacy [25].

References