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To study the role of CD40 ligand (CD40L) in the host immune responses against intracellular pathogens, we infected CD40L knockout (CD40L -/- ) mice with Leishmania amazonensis. Although wild-type mice were susceptible to infection and developed progressive ulcerative lesions, tissue parasite burdens in CD40L -/- mice were significantly higher. This heightened susceptibility...
Using cells from TCR transgenic mice that do or do not express Fas, we show that there are two mechanistically distinct forms of apoptosis in CD4 + T cells. Naive T cells undergo apoptosis if cultured in the absence of antigen or costimulation. This form of programmed cell death (PCD) is not dependent on Fas, and is prevented by CD28-mediated signals, which lead to the secretion of growth...
Interleukin-4 (IL-4) stimulation of cells leads to the activation of multiple signaling pathways, one of which involves Stat6. We have generated Stat6-deficient mice by gene targeting in embryonic stem cells to determine the role of this transcription factor in mediating the biologic functions of IL-4. IL-4-induced increases in the cell surface expression of both MHC class II antigens and IL-4 receptor...
The structure of the human MHC class I molecule H LA- B53 complexed to two nonameric peptide epitopes (from the malaria parasite P. falciparum and the HIV2 gag protein) has been determined by X-ray crystallography at 2.3 Å resolution. The structures reveal the architecture of a Pro-specific B pocket common to many HLA-B alleles. Relative to other alleles, the B53 peptide-binding groove is widened...
The CD40-CD40 ligand (CD40L) signaling process is a pivotal component of multiple immunoregulatory pathways. Although the role that CD40L plays in humoral immune responses is fairly well defined, its function(s) in cell-mediated responses in vivo has not been established. We investigated this issue by assessing the course of Leishmania major infection in CD40L knockout (CD40LKO) mice that were generated...
During B lymphocyte development, pro-B cells that fail to rearrange an immunoglobulin heavy IgH) chain allele productively are thought to undergo developmental arrest and death, but because these cells are short-lived in vivo they are not well characterized. Transgenic mice expressing the apoptosis regulatory gene bcl-x L in the B lineage developed large expansions of pro-B cells in bone marrow...
The crystal structure ofthe human major histocompatibility complex class I B allele HLA B*3501 complexed with the 8-mer peptide epitope HIV1 Nef 75-82 (VPLRPMTY) has been determined at 2.0 Å resolution. Comparison with the crystal structure of the closely related allele HLA B*5301 reveals the structural basis for the tyrosine specificity of the B*3501 F pocket. The structure also reveals a novel conformation...
Covalent attachment of activated products of the third component of complement to antigen enhances its immunogenicity, but the mechanism is not clear. This effect is mediated by specific receptors, mCR1 (CD35) and mCR2 (CD21), expressed primarily on B cells and follicular dendritic cells in mice. To dissect the role of mCR1 and mCR2 in the humoral response, we have disrupted the Cr2 locus to generate...
We and others have defined a transcriptional silencer critical for the proper expression of the CD4 gene at all stages of T cell development. In this report, we use biochemical techniques to identify three different factor-binding sites within the CD4 silencer, denoted sites I, II, and III. Using transgenic analyses, we determine that although all three factor-binding sites are important for silencer...
HLA-DM molecules remove invariant (li) chain peptides from newly synthesized MHC class II complexes. Their localization may thus delineate compartments, e.g., MIIC, specialized for loading peptides onto class II molecules. In murine A20 B cells, however, DM is not restricted to specialized endosomal class II- containing vesicles (CIIV). Although DM was found in CIIV, it was also found throughout the...
CD40-deficient mice are susceptible to Leishmania major infection while their wild-type littermates can resolve the infection. Upon stimulation with L. major antigens, draining lymph node T cells of the mutant mice and the susceptible mice, BALB/c, secrete comparable amounts of IL-4. The mutant mice produce less IFNγ than wild-type mice. The expression of IL-12 p40 mRNA was significantly lower in...
Recent in vitro evidence suggests two alternative mechanisms by which bone marrow-derived APCs may process exogenous antigens for presentation to CTL in vivo, a phenomenon termed cross-priming. Although in vitro studies have suggested that both TAP-dependent and TAP-independent pathways exist, we have now demonstrated an absolute requirement for a functional TAP for cross-priming to occur in vivo...
The death domain of tumor necrosis factor (TNF) receptor-1 (TNFR1) triggers distinct signaling pathways leading to apoptosis and NF-κB activation through its interaction with the death domain protein TRADD. Here, we show that TRADD interacts strongly with RIP, another death domain protein that was shown previously to associate with Fas antigen. We also show that RIP is a serine-threonine kinase that...
Endotoxin shock is the result of activation of the immune system by endotoxin/LPS, a component of Gram-negative bacteria. CD14, a GPI-anchored glycoprotein expressed strongly by monocyte/macrophages, is one of several receptors for endotoxin/LPS. The role of CD14 in bacterial-induced and LPS-induced shock was tested in CD14-deficient mice produced by gene targeting in embryonic stem cells. CD14-deficient...
Roles of the κ intronic enhancer (iEκ) and its asssociated matrix attachment region (MAR) during B cell development were examined using mutant embryonic stem (ES) cell lines in which the entire region on both chromosomes was replaced with either a recombined LoxP site (EκND) or the PGK-neomycin resistance (PGK-neo r ) gene (EκNI). B cells derived from EκND ES cells had greatly impaired VκJκ...
NF-ATp is a member of a family of genes that encodes the cytoplasmic component of the nuclear factor of activated T cells (NF-AT). In this study, we show that mice with a null mutation in the NF-ATp gene have splenomegaly with hyperproliferation of both B and T cells. They also display early defects in the transcription of multiple genes encoding cytokines and cell surface receptors, including CD40L...
A T cell-mediated immune response is mainly determined by the 3-5 aa residues that protrude upwards from a peptide bound to an MHC molecule. Alterations of these peptide residues can diminish, eliminate or radically alter the signal that the T cell receives through its T cell receptor (TCR). We have used peptide immunizations of normal mice and mice carrying α or β chain TCR transgenes to identify...
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