Disease relevance of Tnfrsf8

• We found that CD30, a member of the TNFR-associated factor (TRAF)-linked TNFR superfamily, signaling is involved in differentiation of long-lived CD8+ T(CM) cells following Listeria monocytogenes infection [1].
• At late times but not early in infection, the lymphoid cuff surrounding granulomas was depleted in the CD30-deficient animals [2].
• Impaired negative selection of T cells in Hodgkin's disease antigen CD30-deficient mice [3].
• CD30 is found on Reed-Sternberg cells of Hodgkin's disease and on a variety of non-Hodgkin's lymphoma cells and is up-regulated on cells after Epstein-Barr virus, human T cell leukemia virus, and HIV infections [3].
• Signalling through CD30 protects against autoimmune diabetes mediated by CD8 T cells [4].

High impact information on Tnfrsf8

• We report here that the thymus in CD30-deficient mice contains elevated numbers of thymocytes [3].
• Thus, like TNF-receptors and Fas/Apo-1, the CD30 receptor is involved in cell death signaling [3].
• Here we describe a new mechanism that protects against autoimmunity: this mechanism involves another member of this superfamily, CD30, whose function was largely unknown [4].
• CD30-deficient islet-specific CD8-positive T cells are roughly 6,000-fold more autoaggressive than wild-type cells, with the transfer of as few as 160 CD30-deficient T cells leading to the complete destruction of pancreatic islets and the rapid onset of diabetes [4].
• CD4(+)CD3(-) accessory cells costimulate primed CD4 T cells through OX40 and CD30 at sites where T cells collaborate with B cells [5].

Chemical compound and disease context of Tnfrsf8

• We describe the in vitro and in vivo properties of monoclonal antibody (mAb)-drug conjugates consisting of the potent synthetic dolastatin 10 analogs auristatin E (AE) and monomethylauristatin E (MMAE), linked to the chimeric mAbs cBR96 (specific to Lewis Y on carcinomas) and cAC10 (specific to CD30 on hematological malignancies) [6].
• PURPOSE: To develop a novel targeting reagent to CD30 expressed on Hodgkin'sdisease and anaplastic large cell lymphoma, we made a panel of recombinant immunotoxins specific for CD30 using Fvs of newly produced anti-CD30 monoclonal antibodies (MAbs) and a M(r) 38,000 truncated mutant of Pseudomonas exotoxin [7].

Biological context of Tnfrsf8

• Signaling via CD30 can lead to proliferation or cell death [8].
• A ligand for CD30 has been recently cloned, and has been shown to have sequence homology with the tumor necrosis factor family of cytokines [9].
• Importantly, neither suppression of allograft rejection nor enhanced apoptosis of memory CD8(+) T cells was observed when Treg cells lacked CD30 or when CD30 ligand-CD30 interaction was blocked with anti-CD30 ligand Ab [10].
• Plasma proteomics identified a soluble form of CD30 [11].
• CD30 expression by MD virus (MDV)-transformed lymphocytes correlates with expression of the MDV Meq putative oncogene (a c-Jun homologue) in vivo [11].

Anatomical context of Tnfrsf8

• A novel role of CD30/CD30 ligand signaling in the generation of long-lived memory CD8+ T cells [1].
• CD30-deficient mice showed an impaired capacity to sustain follicular germinal center responses, and recall memory Ab responses were substantially reduced [12].
• Although some TNFR-related molecules are constitutively expressed, others, such as CD30 and Ox40, are induced upon activation of lymphocytes [13].
• We show that, in the absence of CD30 signalling, cells activated but not yet deleted by the CD95-dependent cross-tolerance mechanism gain the ability to proliferate extensively upon secondary encounter with antigen on parenchymal tissues, such as the pancreatic islets [4].
• Chromosomal translocation t(2;5) and the resulting fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) are detected in 50% to 70% of anaplastic large cell lymphoma (ALCL), which is a T/null cell non-Hodgkin's lymphoma showing anaplastic morphology with cell surface expression of CD30 [14].

Associations of Tnfrsf8 with chemical compounds

• In vitro, in the absence of CD30 ligation, thymocytes of CD30 Tg mice have normal survival and responses to apoptotic stimuli such as radiation, dexamethasone, and Fas [15].
• Ki-A10-negative cells were treated with 5-aza-2'-deoxycytidine [16].
• AdoHcy and c3AdoHcy were found to be competitive inhibitors (with Ki values of 1.7 and 4.8 mM, respectively) of the high-affinity cyclic AMP phosphodiesterase present in lymphocyte homogenates [17].
• One with high affinity for cyclic GMP was strongly inhibited (Ki = 10 microM) by NPT 15392 [18].
• The isoquinolinesulfonamide PKC inhibitors H-7 and H-8 inhibit primary, in vivo generated cytotoxic T lymphocyte (CTL) activity by 50% at concentrations approximating their reported Ki values for PKC, 6 uM and 15 uM respectively [19].

Regulatory relationships of Tnfrsf8

• The pleiotropic functions of CD30 are initiated by interaction of CD30-expressing cells with other immune competent cells expressing CD30-L and providing the signals for modulation of effector cell activity [20].
• These results suggest a role for CD30 in regulating the onset of apoptosis in CD8 T cells after interruption of CD3/TCR [21].
• In this study, we report that unlike CD28, ligation of CD30 on normal effector T cells induces IL-13 production in the absence of concurrent TCR engagement [22].

Other interactions of Tnfrsf8

• Although expression of both receptors is augmented by interleukin-4, only CD30 expression is dependent on signal transducer and activator of transcription (STAT)-6-mediated signaling [13].
• However, in contrast to CD30, Ox40 was also expressed on T(h)1 cells [13].
• CD30 overexpression enhances negative selection in the thymus and mediates programmed cell death via a Bcl-2-sensitive pathway [15].
• Regulation of lymphocyte clustering by CD30-mediated ICAM-1 up-regulation [20].
• Given its role in protecting against autoimmunity, one or more of the coding variants within CD30 is a good candidate for the Idd9.2 etiological variant [23].

Analytical, diagnostic and therapeutic context of Tnfrsf8

• CD4+CD25+ regulatory T cells suppress allograft rejection mediated by memory CD8+ T cells via a CD30-dependent mechanism [10].
• The immunoprecipitation study with 3G12 demonstrated a major band of 200 kD and a minor band of 100 kD, which were different from CD30 [24].
• The chimeric anti-CD30 IgG1, cAC10, conjugated to eight equivalents of monomethyl auristatin E (MMAE) was previously shown to have potent antitumor activity against CD30-expressing tumors xenografts in mice [25].
• To overcome shedding-dependent damage of normal cells in CD30-specific immunotherapy, we analyzed the mechanism involved in the release [26].
• In coculture experiments, the antibody-induced transfer of sCD30 from the human Hodgkin's lymphoma cell line L540 to the CD30-negative but CD153-expressing human mast cell line HMC-1 was inhibited by GI254023X [26].

References