The agonistic anti-human CD3 antibody , OKT-3, has been used to control acute transplant rejection. The in vivo administration of OKT-3 was previously shown to induce the partial depletion of T cells and anergy in the remaining CD4+ T cells. However, this therapy is also associated with the systemic release of several cytokines, which leads to a series of adverse side effects. We established a novel anti-human CD3 Ab, 20-2b2 (#1 abs), which recognized a close, but different determinant on the CD3 molecule from that recognized by OKT3. 20-2b2 was non-mitogenic for human CD4+ T cells, could inhibit the activation of T cells in vitro, and induced T cell anergy in in vivo experiments using humanized mice. Cytokine release in humanized mice induced by the administration of 20-2b2 was significantly less than that induced by OKT-3. Our results indicated that the CD3 molecule is still an attractive, effective, and useful target for the modulation of T cell responses. The establishment of other Abs that recognize CD3, even though the determinant recognized by those Abs may be close to or different from that recognized by OKT-3, may represent a novel approach for the development of safer Ab therapies using anti-CD3 Abs, in addition to the modification of OKT-3 in terms of the induction of cytokine production.
Modulation of the human T cell response by a novel non-mitogenic anti-CD3 antibody.
Specimen part, Disease, Disease stage
View SamplesWe found that a number of Tfh cells downmodulated BCL6 protein after their development, and we sought to compare the gene expression between BCL6-hi Tfh cells and BCL6-low Tfh cells.
Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity.
Specimen part
View SamplesTo obtain insight into the genetic basis of the increase of functional activity of memory B cells over time, we compared the gene expression profiles of day 7 and day 40 NP-specific/IgG1 memory B cells, GC B cells and plasma cells in immunized WT mice and nave B cells, before and after activation in vitro.
Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory.
Sex, Age, Specimen part
View SamplesBcl6 germline deletion causes a prominent inflammatory disease, owing to over-expression of Th2 cytokines, and affects the properties of B cells prior to immunization. Therefore we established the B cell-specific Bcl6 deletion mice and analyze the gene expression of naive B cells under physiological conditions.
Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory.
Sex, Age
View SamplesThe Arabidopsis RWP-RK protein RKD4 is expressed specifically in early embryogenesis and triggers embryonic cell division sequences. We used Affymetrix ATH1 microarrays to analyze the pattern of gene expression changes in response to induced ectopic expression of RKD4 in post-embryonic organs.
The Arabidopsis RWP-RK protein RKD4 triggers gene expression and pattern formation in early embryogenesis.
Specimen part, Disease
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Srf destabilizes cellular identity by suppressing cell-type-specific gene expression programs.
Specimen part
View SamplesMulticellular organisms consist of multiple cell types, whose identities are maintained appropriately at locations where they are reside. The identity of each cell type is primarily maintained by cell-type-specific gene expression programs, but mechanisms that suppress these programs are poorly defined. Here we show that serum response factor (Srf), a transcription factor that is activated by various extracellular stimuli, can repress cell-type-specific genes and promote cellular reprogramming to pluripotency. Manipulations that decrease -actin monomer resulted in nuclear accumulation of Mkl1 and the activation of Srf, which downregulated cell-type-specific genes and altered epigenetics in enhancers and chromatin organization. Mice overexpressing Srf exhibited various pathologies including an ulcerative colitis-like symptom and a metaplasia-like phenotype in the pancreas. Our results demonstrate an unexpected function of Srf via a mechanism by which extracellular stimuli actively destabilize cell identity and suggest Srf involvement in a wide range of diseases.
Srf destabilizes cellular identity by suppressing cell-type-specific gene expression programs.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
OVOL2 Maintains the Transcriptional Program of Human Corneal Epithelium by Suppressing Epithelial-to-Mesenchymal Transition.
Specimen part, Cell line
View SamplesIn development, embryonic ectoderm differentiates into several lineages including neuroectoderm and surface ectoderm, through the mechanism largely unclear. Here we report that OVOL2 is required for the transcriptional program of corneal epithelium cell(CEC)s, a derivative of surface ectoderm, and it might regulates the differential transcriptional programs between the two lineages. By a functional screening, we identified transcription factors (TFs) maintaining human CECs. OVOL2 was necessary to maintain the transcriptional program in CECs, particularly through repressing expression of mesenchymal genes. OVOL2 combined with several TFs were able to activate the transcriptional program of CECs in fibroblasts, accompanied by induction of chromatin landscape. Moreover, our analysis revealed that neuroectoderm derivatives express some of mesenchymal genes. In fact, OVOL2 alone was able to induce the transcriptional program of CECs in neural progenitor cells (NPCs) through repression of mesenchymal genes as well as activation of epithelial genes. Our data suggest that the difference between the transcriptional programs of surface ectoderm-derivatives and neuroectoderm-derivatives is regulated in part by the reciprocally-repressive mechanism between epithelial and mesenchymal genes that is seen in epithelial-to-mesenchymal transition.
OVOL2 Maintains the Transcriptional Program of Human Corneal Epithelium by Suppressing Epithelial-to-Mesenchymal Transition.
Specimen part
View SamplesAmmonia is a toxic by-product of metabolism that causes cellular stress. Although a number of proteins are involved in adaptive stress response, specific factors that counteract ammonia-induced cellular stress and regulate cell metabolism that facilitate survival against toxicity have yet to be identified. We demonstrated that hypoxia-inducible factor-1 (HIF-1) is stabilised and activated by ammonia stress. HIF-1 activated by ammonium chloride compromises ammonia-induced apoptosis. Furthermore, we identified glutamine synthetase (GS) as a key driver of cancer cell proliferation and glutamine-dependent metabolism under ammonia stress in ovarian cancer stem-like cells expressing CD90. Interestingly, activated HIF-1 counteracts glutamine synthetase function in glutamine metabolism by facilitating glycolysis and elevating glucose dependency. Our studies reveal the hitherto unknown functions of HIF-1 in biphasic ammonia stress management in cancer stem-like cells. GS facilitates proliferation and HIF-1 contributes to metabolic remodelling in cellular energy usage resulting in attenuated proliferation but conversely promoting cell survival.
Hypoxia-inducible factor-1α promotes cell survival during ammonia stress response in ovarian cancer stem-like cells.
Specimen part, Cell line
View Samples