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While much is known about intracellular signaling events in T cells when T cell receptors (TCRs) are engaged, the mechanism by which signaling is initiated is unclear. We have constructed defined oligomers of soluble antigen-major histocompatibilitycomplex (MHC) molecules, the natural ligands for the TCR. Using these to stimulate specific T cells in vitro, we find that agonist peptide/MHC ligands...
Physiologically, TCR signaling is unlikely to result from the cross-linking of TCR-CD3 complexes, given the low density of specific peptide-MHC complexes on antigen-presenting cells. We therefore have tested directly an alternative model for antigen recognition. We show that monomers of soluble peptide-MHC trigger Ca 2+ responses in CD8αβ + T cells. This response is not observed...
CD4 and CD8 are crucial for the development and function of T cells. An intergenic deoxyribonuclease I hypersensitive site region (cluster CIII) directs expression in mature CD8 T cells only. Here, we show that two further independent regions from the CD8 gene locus in conjunction with cluster CIII restore transgene expression in appropriate immature thymocytes. Deletion of two of the intergenic cluster...
mel-18 is a mammalian Polycomb group gene encoding a transcriptional repressor with tumor suppressive activity. Overexpression of mel-18 in mice results in cell cycle arrest of B cells upon B cell receptor stimulation with downregulation of c-myc. This phenotype is rescued in mel-18/c-myc double-transgenic mice, suggesting that c-myc locates downstream of mel-18. In mel-18 transgenic mice, the downregulation...
The functional status of CD4 + T cells during establishment of persistent infection with the noncytopathic lymphocytic choriomeningitis virus was assessed and compared to that of cytotoxic CD8 + T cells. Functionality of virus-specific CD4 + T cells was measured by proliferative responses, cytokine secretion, cognate help, and IFNγ-mediated protection against challenge infection...
A novel 75 kDa membrane protein, TIRC7, is described that exhibits a central role in T cell activation in vitro and in vivo. Modulation of TIRC7-mediated signals with specific anti-TIRC7 antibodies in vitro efficiently prevents human T cell proliferation and IL-2 secretion. Moreover, anti-TIRC7 antibodies specifically inhibit type 1 subset specific IFN-γ expression but spare the type 2 cytokine IL-4...
We and others have recently identified a CD8 locus enhancer (E8 I ) that directs expression in mature CD8 single-positive thymocytes and peripheral CD8 + T cells and in extrathymically derived intestinal intraepithelial lymphocytes (IEL). In this study, we show that deletion of E8 I by homologous recombination results in reduced CD8αα homodimer expression on IEL Since CD8 expression...
Clonal selection of T lymphocytes is essential for establishing self/non-self discrimination of immune recognition. It is known that cell surface signals such as avidity and valency of TCR-ligand interactions influence the fate of individual thymocytes, founding a primary repertoire of T cells. However, intracellular signals that govern positive and negative selection in the thymus have been unclear...
Precursor CD4 + T cells develop into effector Th1 and Th2 cells that play a central role in the immune response. We show that the JNK MAP kinase pathway is induced in Th1 but not in Th2 effector cells upon antigen stimulation. Further, the differentiation of precursor CD4 + T cells into effector Th1 but not Th2 cells is impaired in JNK2-deficient mice. The inability of IL-12 to differentiate...
Aiolos encodes a zinc finger DNA-binding protein that is highly expressed in mature B cells and is homologous to Ikaros. In the periphery of mice homozygous for an Aiolos-null mutation, B cells exhibit an activated cell surface phenotype and undergo augmented antigen receptor (BCR)-mediated in vitro proliferative responses, even at limiting amounts of stimulant. In vivo, T cell-dependent B cell responses,...
We describe antagonist peptides that specifically inhibit cytolytic activity of T cell clones and lines that express the antigen-specific receptor of CD8 + T lymphocyte clone 2C, which recognizes peptides in association with syngeneic (K b ) and allogeneic (L d ) MHC proteins. Addition of an antagonist peptide that can bind to K b on 2C cells decreased the tyrosine...
The crystal structure of the two immunoglobulin variable-like domains of the murine CD8αα homodimer complexed to the class I MHC H-2K b molecule at 2.8 Å resolution shows that CD8αα binds to the protruding MHC α3 domain loop in an antibody-like manner. Comparison of mouse CD8αα/H-2K b and human CD8αα/HLA-A2 complexes reveals shared as well as species-specific recognition features....
In type III bare lymphocyte syndrome (BLS) patients, defects in the RFX protein complex result in a lack of MHC class II and reduced MHC class I cell surface expression. Using type III BLS cell lines, we demonstrate that the RFX subunits RFX5 and RFXAP are crucial for constitutive and CIITA-induced MHC class I and β 2 m transactivation. Similar to MHC class II, the promoters of MHC class I...
In this report we have investigated the role of the Ets-1 transcription factor in the differentiation of the NK cell lineage in mice. Splenic NK cells express high levels of Ets-1. Ets-1-deficient mice produced by gene targeting developed mature erythrocytes, monocytes, neutrophils, and T and B lymphocytes. However, spleens from the Ets-1-deficient mice contained significantly reduced numbers of natural...
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