Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.2.1.17 (lysozyme)
21,489 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To study the relation between the form of an Ag and the response to it, we compared presentation in vitro with hen egg lysozyme (HEL)-specific T cells from TCR transgenic mice of free HEL and liposome-encapsulated HEL by different APC. HEL-specific splenic B cells or bone marrow-derived dendritic cells were incubated with free HEL or HEL-containing liposomes targeted by Ab to either surface Ig, the Fc receptor, or MHC class I and II molecules. Ag presentation by HEL-specific B cells was at least 100-fold more efficient for HEL in surface Ig-targeted liposomes than free HEL taken up by the same receptor or HEL in liposomes targeted to class I or II molecules. Ag presentation by dendritic cells from Fc receptor-targeted vesicles was augmented 1,000-10,000-fold compared with free Ag or nontargeted liposomes, but presentation was also efficient when Ag was targeted to class I or II molecules. These results indicate that Ag-specific B cells and dendritic cells can be equally efficient in stimulating IL-2 production by Ag-specific T cells from unimmunized TCR transgenic mice when the Ag is multivalent and taken up by appropriate receptors. In contrast to B cells, which require engagement of surface Ig for optimal presentation, dendritic cells may present Ag by means of several different cell surface molecules.
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PMID:Efficient presentation of multivalent antigens targeted to various cell surface molecules of dendritic cells and surface Ig of antigen-specific B cells. 983 89

Co-culture of purified T and B cells obtained from cytochrome c-specific TCR- and hen egg lysozyme (HEL)-specific Ig-transgenic mice was used to examine the role of B cell receptor (BCR) ligation and TCR affinity on the efficiency of T-B cell collaboration. The results showed that BCR ligation of naive B cells with HEL was not required for effective presentation of high-affinity antigen to T cells, although it did enhance activation and division of both T and B cells. Anergic B cells were also effective at presentation of high-affinity antigen and proliferated more than naive B cells in response to T cell help, due to prior exposure to antigen in vivo. Despite the fact that induction of CD86 on anergic B cells following BCR ligation was suboptimal, these cells supported T cell activation and survival in culture as efficiently as naive B cells exposed to HEL. In contrast, when the low-affinity antigen mls-3a served as the T cell stimulus, BCR ligation was essential to elicit a detectable T cell response. Thus the in vitro model demonstrates that co-stimulation is not an absolute requirement for effective antigen presentation and delivery of T cell help to B cells. Rather, the cooperative effects of BCR ligation and TCR affinity determine the relative requirement for co-stimulation.
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PMID:Influence of B cell receptor ligation and TCR affinity on T-B collaboration in vitro. 986 40

A bound conformation of the antigenic decapeptide hen egg lysozyme HEL[52-61] associated to the mouse MHC class II (MHC II) I-Ak was modeled by homology with the three-dimensional structure of hemagglutinin HA[306-318]-HLA-DR1 complex. HEL peptide Tyr53 could not be aligned with the HA peptide Tyr308 because this resulted in a buried Tyr53 side chain within the I-Ak peptide-binding groove and this conflicted with this side chain being recognized by T cells. Therefore, Asp52 of HEL was fixed as the P1 anchor and aligned on Tyr308 of HA. After molecular dynamics, the modeled complex was stable even in the absence of any constraint. The peptide backbone adopted a polyproline II-like conformation with canonical hydrogen bonding between the peptide backbone and MHC II molecule. Asp52, IIe55, Gin57 and Ser60 were predicted to be deeply buried into P1, P4, P6 and P9 MHC II pockets, and Tyr53, Leu56, Asn59 and Arg61 as TCR contacting residues. The modeling of 15 complexes associating I-Ak with peptides derived from HEL[52-61] by single amino acid substitution proved stable with conserved hydrogen bonds and side chain orientation compatible with their recognition by two T cell hybridomas. Moreover, comparison with the recently solved crystal structure of the related HEL[50-62]-I-Ak complex revealed striking similarities.
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PMID:Molecular modeling of hen egg lysozyme HEL[52-61] peptide binding to I-Ak MHC class II molecule. 988 96

In mice with a diverse B cell repertoire, hen egg lysozyme (HEL) autoantigen-binding B cells are excluded from follicles and eliminated in 3 days. To explore the roles of competitor B cells and of T cells in this mechanism of self-tolerance, HEL-specific B cells were transferred into mice containing HEL and deficient in endogenous B cells (muMT), T cells (TCR-/-), or B and T cells (RAG1-/-). Previous studies suggested a dual requirement for B cell receptor (BCR) engagement and competition in HEL autoantigen-binding B cell elimination, but interpretation of these experiments has been confounded by the possible failure to independently regulate autoantigen concentration and competitor B cell frequency. In experiments in this study, we have fixed one variable, HEL concentration, while varying the second, the presence or absence of other B cells. By this approach, we find that follicular exclusion and rapid elimination of autoreactive B cells require BCR engagement plus competition with other B cells, rather than BCR engagement alone. We also find, by transfers into T cell-deficient mice, that T cells are not required for this peripheral tolerance mechanism. Unexpectedly, in mice lacking both T cells and competitor B cells (RAG1-/-), transferred HEL-binding cells survive less well than in mice just lacking competitor B cells. These results suggest T cells can enhance autoreactive B cell survival. Enhanced survival of autoreactive B cells, due to the presence of T cells and the lack of competitor B cells, might contribute to the elevated frequency of autoimmunity in B cell-deficient individuals.
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PMID:Follicular exclusion and rapid elimination of hen egg lysozyme autoantigen-binding B cells are dependent on competitor B cells, but not on T cells. 988 97

The 3A9 transgenic mouse line carries the rearranged TCR genes from a T cell hybridoma that recognizes hen egg lysozyme peptide 46-61 in the context of MHC class II Ak molecules. As expected, positive selection of immature 3A9 thymocytes to become mature CD4+ 8- T cells was efficient on the "selecting" CBA (H-2k) genetic background but not on the "non-selecting" C57BL/6 (H-2b) background. Surprisingly, positive selection was also inefficient on the CBA x C57BL/6 F1 background (H-2kb). We present evidence that expression of A(beta)b molecules on thymus epithelium (in conjunction with A(alpha)b or A(alpha)k molecules) inhibits the positive selection of 3A9 thymocytes mediated by A(alpha)k:A(beta)k complexes, in a process evocative of peptide antagonism of mature T cells.
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PMID:Inhibition of thymocyte positive selection by natural MHC: peptide ligands. 1006 54

The establishment of CD4(+) T cell tolerance requires that self-reactive thymocytes are negatively selected during thymic development. A threshold of antigen concentration appears to exist for both MHC class I- and class II-mediated negative selection, below which clonal deletion of a self-reactive transgenic TCR does not occur. Similarly, both the specificity and thymic concentration of MHC molecules affect the efficiency with which autoreactive thymocytes are deleted. However, this threshold for MHC class II concentration has not been well established. Here, we show that this threshold must be extraordinarily low. We have used the human lysozyme promoter to re-express an A(beta)(b) cDNA on macrophages and other phagocytic myelomonocytic cells of class II-deficient A(beta)(b) -/- mice. Surface expression of I-A(b) could be detected on mature peritoneal macrophages and, minimally, on thymic dendritic cells; however, this level of expression was not sufficient for antigen-specific T cell activation. Nevertheless, when backcrossed onto an autoreactive K14 background, this minimal level of class II was sufficient to induce negative selection of a polyclonal self-reactive population. We conclude that provision of extremely low levels of class II to thymic dendritic cells confers on them the ability to mediate clonal deletion of autoreactive T cells.
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PMID:A minimal level of MHC class II expression is sufficient to abrogate autoreactivity. 1042 87

T cells expressing two different TCRs were generated by interbreeding 3A9 and AND CD4+ TCR transgenic mice specific for the hen egg lysozyme (HEL) peptide 48-62:I-Ak and moth cytochrome c (MCC) peptide 88-103:I-Ek peptide:MHC ligands, respectively. Peripheral T cells in the offspring express two TCR V beta-chains and respond to HEL and MCC. We observed minimal or no additive effects upon simultaneous suboptimal stimulation with both agonist peptides; however, an antagonist peptide for the 3A9 TCR was able to inhibit the response of the dual receptor T cells to MCC, the AND TCR agonist. This HEL antagonist peptide did not affect AND single transgenic T cells, indicating that the antagonism observed in the dual TCR cells is dependent on the presence of the HEL-specific 3A9 TCR. In contrast, anti-TCR Abs mediate receptor-specific antagonism. These results demonstrate that peptide antagonism exerts a dominant effect.
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PMID:Cutting edge: dueling TCRs: peptide antagonism of CD4+ T cells with dual antigen specificities. 1043 5

In vitro and in vivo activation of T cells was investigated with invariant chain-antigen fusion protein. The CD4 T cell epitope amino acid 52-61 of hen egg lysozyme (HEL) was attached to the C-terminal end of invariant chain (Ii). Expression of this recombinant Ii HEL directs the T cell epitope to the class II processing pathway. Class II molecules of transfected antigen presenting cells (APC) are charged with this HEL epitope. The endogenously provided epitope competes with processing and presentation of exogenously added antigen. APC expressing recombinant Ii HEL stimulate a maximal IL-2 response of HEL-specific T hybridoma cells. Nonprofessional APC expressing recombinant Ii HEL and H2-Ak are also able to activate naive T cells from 3A9 TCR transgenic mice, a result not achieved with peptide pulsed APC. To elicit an in vivo immune response dendritic cells (DC) were transfected with rIi HEL cDNA: following immunization of CBA mice with transfected DC, a primary T cell response against the HEL epitope was induced. Thus the procedure described here could be used to introduce antigens into the class II processing pathway and to elicit T cell activation both in vitro and in vivo.
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PMID:C-terminal extension of the MHC class II-associated invariant chain by an antigenic sequence triggers activation of naive T cells. 1060 78

The Ag processing and structural requirements involved in the generation of a major T cell epitope from the hen egg-white lysozyme protein (HEL74-88), containing two cysteine residues at positions 76 and 80, were investigated. Several T cell hybridomas derived from both low responder (I-Ab) and high responder (I-Ak) mice recognize this region. These hybridomas are strongly responsive to native HEL, but unresponsive to the reduced and carboxymethylated protein. Air-oxidized HEL74-88 peptide was unable to bind I-Ak molecules and failed to stimulate T cells in the absence of intracellular Ag processing. Further functional competition assays showed that alkylation of cysteine residues with bulky methyl groups interferes with the contacts for the MHC class II molecules (I-Ak) of high responder mice and the I-Ab-restricted TCR of low responder mice. Serine substitutions of the cysteine residues of HEL74-88 either enhanced or abrogated T cell stimulation by the peptides without significant alterations in the class II binding. These results suggest that the cysteine residues of peptides must be free from disulfide bonding for efficient stimulation of T cells and yet frequently used modifications of cysteine residues may not be suitable for peptide-based vaccine development.
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PMID:Processing and reactivity of T cell epitopes containing two cysteine residues from hen egg-white lysozyme (HEL74-90). 1065 24

The relative ability of Th1 and Th2 T cells to help B cells remains controversial as do the mechanisms by which both T cell subsets provide help in vivo. Whether this help affects the clonal expansion and/or differentiation of B cells has been difficult to assess due to the low frequency of Ag-specific T and B lymphocytes. We have employed a novel technique to directly monitor the clonal expansion of Ag-specific T and B lymphocytes in vivo. OVA-specific TCR transgenic T lymphocytes were polarized toward a Th1 or Th2 phenotype in vitro. These cells were then transferred into syngeneic recipients, along with B cell receptor transgenic hen egg lysozyme-specific B lymphocytes. Our results indicate that Th1 and Th2 cells support B cell responses to a similar extent in vivo and that they achieve this in the same manner by migrating into B cell follicles to promote CD154-dependent B cell clonal expansion and Ab production.
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PMID:Th1 and Th2 CD4+ T cells provide help for B cell clonal expansion and antibody synthesis in a similar manner in vivo. 1097 27


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