Cross reactivity among the ligands of the 7 helix family.

"Specific" drugs for receptors of the 7 helix family inhibited in high doses other receptors of the same family, as well. Atropine inhibited [3-H]-clonidine binding, beta-adrenergic drugs: propranolol, betoxalol, ICI 118.551 inhibited labelled QNB binding to all the 3 main subtypes of muscarinic receptors. Authors propose the existence of common features in the ligand binding sites of the receptors of 7 helix family.     

Evolution of the B7 family: co-evolution of B7H6 and NKp30, identification of a new B7 family member, B7H7, and of B7's historical relationship with the MHC

The B7 family of genes is essential in the regulation of the adaptive immune system. Most B7 family members contain both variable (V)- and constant (C)-type domains of the immunoglobulin superfamily (IgSF). Through in silico screening of the Xenopus genome and subsequent phylogenetic analysis, we found novel genes belonging to the B7 family, one of which is the recently discovered B7H6. Humans and rats have a single B7H6 gene; however, many B7H6 genes were detected in a single large cluster in the Xenopus genome. The B7H6 expression patterns also varied in a species-specific manner. Human B7H6 binds to the activating natural killer receptor, NKp30. While the NKp30 gene is single-copy and maps to the MHC in most vertebrates, many Xenopus NKp30 genes were found in a cluster on a separate chromosome that does not harbor the MHC. Indeed, in all species so far analyzed from sharks to mammals, the number of NKp30 and B7H6 genes correlates well, suggestive of receptor-ligand co-evolution. Furthermore, we identified a Xenopus-specific B7 homolog (B7HXen) and revealed its close linkage to B2M, which we have demonstrated previously to have been originally encoded in the MHC. Thus, our study provides further proof that the B7 precursor was included in the proto MHC. Additionally, the comparative analysis revealed a new B7 family member, B7H7, which was previously designated in the literature as an unknown gene, HHLA2.     

The expression, function, and clinical relevance of B7 family members in cancer

The modulation and suppression of anti-tumor immune responses is a characteristic feature of tumor cells to escape immune surveillance. Members of the B7 family are involved in this process, since the level of activation of the anti-tumor immune response depends on the balance between co-stimulatory and co-inhibitory signals. Some molecules are often overexpressed in tumors, which has been associated with the pathogenesis and progression of malignancies as well as their immunological and non-immunological functions. The B7 homologs play a key role in the maintenance of self-tolerance and the regulation of both innate and adaptive immunity in tumor-bearing hosts. Furthermore, the blockade of negative signals mediated by the interaction of co-inhibitory ligands and counter-receptors of the B7 family is currently being studied as a potential immunotherapeutic strategy for the treatment of cancer in humans.     

Comprehensive molecular profiling of the B7 family in gastrointestinal cancer

Objectives

B7 family has been identified as co‐stimulatory or co‐inhibitory molecules on T‐cell response and plays an important role in tumour mortality and malignancy. In this study, the expression pattern of B7 family in gastrointestinal (GI) cancer was examined. Its upstream regulating mechanism, downstream targets and association with clinical parameters were also studied.

Materials and methods

The expression level of B7 members was analysed by FIREHOUSE. The gene mutation, DNA methylation, association with clinical parameters and downstream network of B7 members were analysed in cBioportal. The mutation frequency was analysed by Catalogue of Somatic Mutations in Cancer (COSMIC) analysis. The phylogenetic tree was constructed in MEGA7. The interaction protein domain analysis was performed by Pfam 31.0.

Results

Differential expression of B7 family molecules was detected in different kinds of GI cancer. High‐frequency gene alteration was found in tumour samples. There was negative correlation of promoter methylation and mRNA expression of B7 family members in tumour samples, suggesting the epigenetic basis of B7 family gene deregulation in GI cancer. The overexpression of B7‐H1 in pancreatic cancer, B7‐H5 in oesophageal cancer and B7‐H6 in liver cancer were significantly associated with worse overall survival. Finally, by network analysis, we identified some potential interacting proteins for B7‐1/2 and B7‐H1/DC.

Conclusions

Overall, our study suggested that B7 member deregulation was strongly involved in GI cancer tumorigenesis.

     

Interactions of T cells with fibroblast-like synoviocytes: role of the B7 family costimulatory ligand B7-H3

Fibroblast-like synoviocytes (FLS) and T cells can activate each other in vitro, and in vivo interactions between these cells may be important in rheumatoid arthritis (RA), yet FLS lack significant expression of CD28 ligands. We sought to identify molecules homologous to CD28 ligands that are strongly expressed by FLS, and documented strong B7-H3 expression on FLS and by fibroblasts of other tissues, which was unaffected by a variety of cytokines. Western blot analysis of FLS lysates showed predominant expression of the larger, four Ig-like domain isoform of B7-H3. Immunohistological sections of RA synovial tissue showed strong staining for B7-H3 on FLS. Cells expressing B7-H3 were distinct from but in close proximity to cells that expressed CD45, CD20, and CD3. Confocal microscopy of FLS and T cell cocultures showed localization of B7-H3 in the region of the T cell-FLS contact point, but distinct from the localization of T cell CD11a/CD18 (LFA-1) and FLS CD54 (ICAM-1). Reduction of B7-H3 expression on FLS by RNA interference affected interactions of FLS with resting T cells or cytokine-activated T cells. Resting T cells showed increased production of TNF-alpha, IFN-gamma, and IL-2, whereas cytokine-activated T cells showed reduced cytokine production relative to control. However, cytokine production by T cells activated through their TCR was not notably altered by knock down of B7-H3. These observations suggest that B7-H3 may be important for the interactions between FLS and T cells in RA, as well as other diseases, and the outcome of such interactions depends on the activation state of the T cell.     

A growing family of Notch ligands

Signaling through Notch-like receptors is an evolutionarily well-conserved mechanism for cell-cell communication. Transmembrane ligands of the DSL (Delta, Serrate, LAG-2) family signal to Notch receptors on a neighboring cell, which results in an intracellular signaling cascade, influencing cellular differentiation. Recently published data shed new light on the repertoire of ligands and on processing of Notch receptors. One report provides evidence for a novel, more distantly related ligand of the Delta-type in mouse, Dll3 (Delta-like 3)¹. Ectopic expression of Dll3 perturbs primary neurogenesis in frog embryos in a manner expected for a bona fide Notch ligand. Two reports provide new information about processing of Notch receptors. A novel protease, Kuzbanian, is identified, which cleaves the Notch receptor at the extracellular side². Biochemical experiments show that the cleavage probably occurs during intracellular trafficking, and that only processed Notch receptors appear at the cell surface³. Taken together, these reports extend our knowledge about an important event in cell-cell communication—how Notch ligands and receptors meet and interact. BioEssays 20:103–107, 1998. © 1998 John Wiley & Sons, Inc.     

The EGF-TM7 family of the rat

EGF-TM7 receptors are adhesion class heptahelical molecules predominantly expressed by cells of the immune system. Based on an analysis of the recently unraveled genome, the EGF-TM7 family of the rat is described here. Like the mouse, the rat has three EGF-TM7 receptors—CD97, EMR1 and EMR4. The highest conservation between the orthologues lies within the membrane-spanning part and emphasizes the functional importance of this region.The nucleotide sequences reported here have been submitted to the GenBank database with the following accession numbers: AY686632 and AY686633.     

Extending the B7 (CD80) gene family.

B7-1 and B7-2 are members of the immunoglobulin superfamily (IgSF) and important regulators of T cell-mediated immune responses. Despite sharing only limited sequence identity, B7-1 and B7-2 bind common receptors, CD28 and CTLA-4, on T cells and have similar functional properties. We have found that the extracellular V (ariable)-like domains of B7-1 and B7-2 share significant sequence similarities with 3 major histocompatibility complex (MHC)-encoded members of the IgSF: butyrophilin, myelin/oligodendrocyte glycoprotein, and the chicken MHC molecule, B-G. This raises the question whether there is an evolutionary link between the MHC, which encodes molecules regulating the antigen specificity of T lymphocyte responses, and B7 molecules, which co-stimulate these responses in antigen-nonspecific fashion.     

B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion

The B7 family members B7-1 and B7-2 interact with CD28 and constitute an essential T-cell co-stimulatory pathway in the initiation of antigen-specific humoral and cell-mediated immune response. Here, we describe a third member of the B7 family, called B7-H1 that does not bind CD28, cytotoxic T-lymphocyte A4 or ICOS (inducible co-stimulator). Ligation of B7-H1 co-stimulated T-cell responses to polyclonal stimuli and allogeneic antigens, and preferentially stimulated the production of interleukin-10. Interleukin-2, although produced in small amounts, was required for the effect of B7-H1 co-stimulation. Our studies thus define a previously unknown co-stimulatory molecule that may be involved in the negative regulation of cell-mediated immune responses.     

The GDNF family ligands and receptors - implications for neural development

The glial cell line derived neurotrophic factor (GDNF) family has recently been expanded to include four members, and the interactions between these neurotrophic factors and their unique receptor system is now beginning to be understood. Furthermore, analysis of mice lacking the genes for GDNF, neurturin, and their related receptors has confirmed the importance of these factors in neurodevelopment. The results of such analyses reveal numerous similarities and potential overlaps in the way the GDNF and the nerve growth factor (NGF) families regulate development of the peripheral nervous system.     

The EGF-TM7 family: a postgenomic view

With the human and mouse genome projects now completed, the receptor repertoire of mammalian cells has finally been elucidated. The EGF-TM7 receptors are a family of class B seven-span transmembrane (TM7) receptors predominantly expressed by cells of the immune system. Within the large TM7 superfamily, the molecular structure and ligand-binding properties of EGF-TM7 receptors are unique. Derived from the processing of a single polypeptide, they are expressed at the cell surface as heterodimers consisting of a large extracellular region associated with a TM7 moiety. Through a variable number of N-terminal epidermal growth factor (EGF)-like domains, EGF-TM7 receptors interact with cellular ligands such as CD55 and chondroitin sulfate. Recent in vivo studies demonstrate a role of the EGF-TM7 receptor CD97 in leukocyte migration. The different number of EGF-TM7 genes in man compared with mice, the chimeric nature of EMR2 and the inactivation of human EMR4 point toward a still-evolving receptor family. Here we discuss the currently available information on this intriguing receptor family.     

The B7-CD28 superfamily

The B7-1/B7-2-CD28/CTLA-4 pathway is crucial in regulating T-cell activation and tolerance. New B7 and CD28 molecules have recently been discovered and new pathways have been delineated that seem to be important for regulating the responses of previously activated T cells. Several B7 homologues are expressed on cells other than professional antigen-presenting cells, indicating new mechanisms for regulating T-cell responses in peripheral tissues. Some B7 homologues have unknown receptors, indicating that other immunoregulatory pathways remain to be described. Here, we summarize our current understanding of the new members of the B7 and CD28 families, and discuss their therapeutic potential.     

Effects of specific immunotherapy on the B7 family of costimulatory molecules in allergic inflammation

The effect of allergen-specific immunotherapy (IT) on Ag presentation and T lymphocyte stimulation was evaluated by verifying the expression of costimulatory molecules in allergic patients. Thus, CD28 and CTLA-4, B7, and B7-H molecules on immune cells, as well as cytokine production, were analyzed in and out of the pollination period in 30 patients allergic to Betulaceae that had or had nor undergone specific IT. Results showed that IT attenuated the increase in the percentage of CD28(+)CD4 T cells and the decrease in the percentage of CTLA-4(+)CD4(+) T cells seen in untreated individuals. CD19(+)/CD80, CD19(+)/CD86(+), and CD14(+)/CD80(+) APCs were significantly augmented during pollination in unvaccinated individuals. B7-H1-expressing monocytes (CD14(+)) and B lymphocytes (CD19) as well as CD14 and CD19 B7-H1(+)/IL-10(+) APC were augmented in Betulaceae Ag-stimulated cell cultures of vaccinated patients independently of pollination, and were further increased in these individuals during pollination. As a result, the IL-10-IFN-gamma ratio in CD4(+), CD14(+), and CD19(+) cells increased in vaccinated patients, but decreased in unvaccinated individuals during pollination. These data clarify the cellular and molecular basis underlying the recent observation that peripheral expansion of IL-10-producing cells is associated with successful IT. B7-H1 could be an optimal target for IT of allergic diseases using mAbs.