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Inoculation of plasmid vectors encoding a viral protein into muscle tissue was shown to result in expression of the transantigen and, consequently, an antiviral immune response. Here, we show that coinoculation of a plasmid expressing the glycoprotein of rabies virus with plasmids encoding mouse cytokines modulated the immune response to the viral protein. Coinoculation with a vector expressing mouse...
The superantigen encoded by the mouse mammary tumor virus (MMTV) is a potent stimulator of T cells when bound to MHC class II molecules. Recent data from this laboratory have shown that the Mtv7 superantigen, Mls-1, elicits a strong T cell response when presented by HLA-DR. To expand these observations further, we have produced the 28 kDa extracellular domain and the 18 kDa carboxy-terminal subfragment...
An Epstein-Barr virus—encoded protein, LMP2, blocks the effects of surface immunoglobulin (slg) cross-linking on calcium mobilization and on lytic reactivation of EBV in latently infected and growth-transformed primary human B lymphocytes. In wild-type EBV-transformed cells, LMP2 is constitutively tyrosine phosphorylated and is associated with Lyn and Syk protein-tyrosine kinases (PTKs). Baseline...
In mice injected with superantigens, T cells specific for that antigen proliferate and then die. It has been suggested that the target cells die because they encounter superantigen on the surfaces of nonprofessional presenting cells, such as B cells, which cannot deliver costimulatory signals to T cells. A number of reagents that induce costimulatory molecules on B cells were tested. Lipopolysaccharide...
Human memory B cells that carry mutated IgV region genes were isolated from tonsils by negative selection of IgD + naive B cells and CD38 + germinal center B cells and plasma cells. They were mainly found within the intraepithelial areas, but not in the B cell follicles of human tonsils. Memory B cells but not naive B cells have the capacity to present antigen directly to T cells,...
Alloantigen-stimulated CD8 + mouse spleen cells, either spontaneously or in the presence of IL-12 or IFNγ plus anti-IL-4, differentiate into CD8 + T cells secreting a Th1-like cytokine pattern (IL-2 and IFNγ). IL-4 induced differentiation into CD8 + T cells secreting Th2 cytokines (IL-4, IL-5, IL-6, and IL-10), whereas anti-IFNγ suppressed the development of CD8 + cells...
The receptors for IL-3, GM-CSF, and IL-5 share a common β subunit (βc), and mice have an additional IL-3 β subunit (β IL3 ). We have independently generated mice carrying null mutations of each molecule. βc mutant bone marrow showed no response to GM-CSF or IL-5, whereas IL-3 stimulation of βc or β IL3 mutant bone marrow was normal. βc mutant mice showed lung pathology consisting of...
Disulfide-stabilized Fvs (dsFv) are recombinant Fv fragments of antibodies In which the Inherently unstable V H -V L heterodimer Is stabilized by an Interchain disulfide bond engineered between structurally conserved framework positions. We now design and produce a disulfide-stabilized Fv of a T cell receptor. It is composed of Va and Vβ variable domains of the 2134 TCR stabilized...
The conserved invariant chain associates with highly polymorphic α and β subunits guiding class II transport through the secretory pathway. Early associations of these three polypeptides Inside antigen-presenting cells are poorly understood. The present experiments provide a detailed picture of the structure and fate of class II α and β subunits in invariant chain mutants possessing different MHC...
Memory or antigen-experienced CD4 T cells differ from naive CD4 T cells both phenotypically by cell surface marker expression, and functionally by their dissimilar pattern of cytokine secretion and activation requirements through their T cell receptor (TCR). We show here that activation of memory CD4 T cells (CD45RB lo subset), but not naive CD4 T cells (CD45RB hi subset), is inhibited...
Major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes (CTL) recognize peptide epitopes of protein antigens in a hierarchical fashion. We investigated whether proteolytic cleavage, in particular by proteasomes, Is important in determining epitope hierarchy. Using highly purified 20S proteasomes, we find preferred cleavage sites directly adjacent to the N- and C-terminal...
The common γ chain (γ c ) of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors is defective in humans with XSCID. Mice lacking γ c expression had poplastic thymuses; the thymocytes responded to γ c -independent mitogens, but not γ c -dependent stimuli. Splenic T cells were diminished at 3 weeks of age, but CD4 + T cells markedly increased by 4 weeks. B cells were...
Fas receptor-induced apoptosis plays critical roles in immune homeostasis. However, most of the signal transduction events distal to Fas ligatlon have not been elucidated. Here, we show that Ras is activated following ligation of Fas on lymphoid lines. The activation of Ras is a critical component of this apoptotic pathway, since Inhibition of Ras by neutralizing antibody or a dominant-negative Ras...
Differentiation of Immature CD4 + CD8 + thymocytes into mature CD4 + CD8 − and CD4 − CD8 + T cells requires that synthesis of one or the other coreceptor molecule be terminated, a process referred to as lineage commitment. The present study has utilized a novel coreceptor reexpression assay to identify lineage commitment in immature thymocytes and has...
We demonstrate that cognate peptide ligands altered at T call receptor (TCR) contact residues and bound to class II major histocompetability complex can change the cytokine pattern of mature T cell clones. Myelin basic protein peptide 85–99-reactive Th0 T cell clones were stimulated with altered peptide ligands, which acted both as TCR antagonist and induced new mRNA synthesis and protein secretion...
The present study has examined the molecular events leading to formation of αβ dimers in normal murine thymocytes and mature T cells. We demonstrate that TCR assembly proceeds by initial association of TCRα with CD3δϵ proteins and by association of TCRβ with CD3γϵ proteins to form αδϵ and βγϵ trimers; these trimers then associate to form αδϵ-βγϵ complexes, within which α-β disulfide bond formation...
A key cytokine Induced during the Immune response is IL-2. Following T cell activation, the genes encoding IL-2 and the various chains of Its receptor are transcriptionally induced. In turn, secreted IL-2 serves to stimulate the proliferation and differentiation of T lymphocytes. Several recent studies have implicated Jak kinasea in the signaling pathway Induced by IL-2. Following this lead, we set...
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