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1.
Kim J Kim HR Lee JC Jang YS 《Biochemical and biophysical research communications》2002,291(1):139-145
Substantial evidence suggests that MHC class II molecules play a critical role in transducing signals during B cell activation and differentiation. In addition, we previously found that cross-linking of MHC class II molecules using anti-MHC class II antibodies inhibited NF-kappaB activation in resting B cells isolated from mouse spleen. In this study, we investigated the mechanism of anti-MHC class II antibody-mediated inhibition of LPS-induced NF-kappaB activation using a resting B cell line, 38B9. We found that treatment with a corresponding anti-MHC class II antibody reduced the activation of NF-kappaB in LPS-stimulated 38B9 cells, treatment of the antibody mediated down-regulation of PKC and ERK/p38 MAP kinase pathways, and treatment with PKC inhibitors caused down-regulation of ERK and p38 MAP kinase activities in LPS-stimulated 38B9 cells. Our results suggest that the PKC and ERK/p38 MAP kinase pathways are regulated by anti-MHC class II antibodies, and that MHC class II molecules are actively involved in the signal transduction pathway in the resting B cell line, 38B9. Consequently, disruption of these pathways might contribute to the inhibition of LPS-induced NF-kappaB activation in 38B9 cells. 相似文献
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Resting B lymphocytes have been credited with inducing T cell tolerance to Ig-derived and monovalent self-Ags that are internalized via the B cell receptor (BCR). These conclusions are predicated upon the assumptions that resting B cells display BCR-associated peptides in class II MHC and that the cells remain quiescent during the course of experimental manipulation. To determine whether resting B cells display BCR-associated epitopes in class II MHC, we devised a sensitive assay that averted potential activation of B cells by Ag and minimized activation by prolonged culture. Ex vivo, Percoll-fractionated B cells expressing a kappa transgene encoding a T cell epitope were cultured with a reactive T cell hybridoma for 12 h. Whereas low density, LPS-activated, and BCR-activated B cells elicited significant IL-2 from the T cell hybridoma, resting high density B cells did not. Parallel results were obtained with normal B cells expressing a second epitope encoded by an endogenous V(H) gene. Anergic B cells, which are uniformly low density, also significantly stimulated the T cell hybridoma. Finally, longer culture periods with normal B cells resulted in a higher degree of B cell activation and significant stimulation of reactive T cell hybridomas. Our results provide evidence that activation of B cells profoundly enhances the processing and presentation of BCR-associated Ags. 相似文献
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Ligands binding to Toll-like receptor (TLR), interleukin 1 receptor (IL-1R), or IFN-γR1 are known to trigger MyD88-mediated signaling, which activates pro-inflammatory cytokine responses. Recently we reported that staphylococcal enterotoxins (SEA or SEB), which bind to MHC class II molecules on APCs and cross link T cell receptors, activate MyD88- mediated pro-inflammatory cytokine responses. We also reported that MyD88(-/-) mice were resistant to SE- induced toxic shock and had reduced levels of serum cytokines. In this study, we investigated whether MHC class II- SE interaction by itself is sufficient to activate MyD88 in MHC class II(+) cells and induce downstream pro-inflammatory signaling and production of cytokines such as TNF-α and IL-1β. Here we report that human monocytes treated with SEA, SEB, or anti-MHC class II monoclonal antibodies up regulated MyD88 expression, induced activation of NF-kB, and increased expression of IL-1R1 accessory protein, TNF-α and IL-1β. MyD88 immunoprecipitated from cell extracts after SEB stimulation showed a greater proportion of MyD88 phosphorylation compared to unstimulated cells indicating that MyD88 was a component of intracellular signaling. MyD88 downstream proteins such as IRAK4 and TRAF6 were also up regulated in monocytes after SEB stimulation. In addition to monocytes, primary B cells up regulated MyD88 in response to SEA or SEB stimulation. Importantly, in contrast to primary B cells, MHC class II deficient T2 cells had no change of MyD88 after SEA or SEB stimulation, whereas MHC class II-independent activation of MyD88 was elicited by CpG or LPS. Collectively, these results demonstrate that MHC class II utilizes a MyD88-mediated signaling mechanism when in contact with ligands such as SEs to induce pro-inflammatory cytokines. 相似文献
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Busman-Sahay K Sargent E Harton JA Drake JR 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(12):6710-6717
Previous work established that binding of the 11-5.2 anti-I-A(k) mAb, which recognizes the Ia.2 epitope on I-A(k) class II molecules, elicits MHC class II signaling, whereas binding of two other anti-I-A(k) mAbs that recognize the Ia.17 epitope fail to elicit signaling. Using a biochemical approach, we establish that the Ia.2 epitope recognized by the widely used 11-5.2 mAb defines a subset of cell surface I-A(k) molecules predominantly found within membrane lipid rafts. Functional studies demonstrate that the Ia.2-bearing subset of I-A(k) class II molecules is critically necessary for effective B cell-T cell interactions, especially at low Ag doses, a finding consistent with published studies on the role of raft-resident class II molecules in CD4 T cell activation. Interestingly, B cells expressing recombinant I-A(k) class II molecules possessing a β-chain-tethered hen egg lysosome peptide lack the Ia.2 epitope and fail to partition into lipid rafts. Moreover, cells expressing Ia.2(-) tethered peptide-class II molecules are severely impaired in their ability to present both tethered peptide or peptide derived from exogenous Ag to CD4 T cells. These results establish the Ia.2 epitope as defining a lipid raft-resident MHC class II conformer vital to the initiation of MHC class II-restricted B cell-T cell interactions. 相似文献
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The roles of MHC class II, CD40, and B7 costimulation in CTL induction by plasmid DNA 总被引:4,自引:0,他引:4
Chan K Lee DJ Schubert A Tang CM Crain B Schoenberger SP Corr M 《Journal of immunology (Baltimore, Md. : 1950)》2001,166(5):3061-3066
DNA-based vaccines generate potent CTL responses. The mechanism of T cell stimulation has been attributed to plasmid-transfected dendritic cells. These cells have also been shown to express plasmid-encoded proteins and to become activated by surface marker up-regulation. However, the increased surface expression of CD40 and B7 on these dendritic cells is insufficient to overcome the need for MHC class II-restricted CD4(+) T cell help in the priming of a CTL response. In this study, MHC class II(-/-) mice were unable to generate a CTL response following DNA immunization. This deficit in CTL stimulation by MHC class II-deficient mice was only modestly restored with CD40-activating Ab, suggesting that there were other elements provided by MHC class II-restricted T cell help for CTL induction. CTL activity was also augmented by coinjection with a vector encoding the costimulatory ligand B7.1, but not B7.2. These data indicate that dendritic cells in plasmid DNA-injected mice require conditioning signals from MHC class II-restricted T cells that are both CD40 dependent and independent and that there are different roles for costimulatory molecules that may be involved in inducing optimal CTL activity. 相似文献
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B Dugas N Paul-Eugene J Cairns J Gordon A Calenda J M Mencia-Huerta P Braquet 《Journal of immunology (Baltimore, Md. : 1950)》1990,145(10):3406-3411
This study documents the influence of leukotriene (LT) B4 on human B lymphocyte responses. Incubation of freshly isolated B lymphocytes with LTB4, but not LTC4, induced a slight but significant, time- and dose-dependent increase in the surface expression of Fc epsilon RII/CD23 and class II MHC Ag and in the release of soluble CD23. These changes were maximal at 10 nM LTB4 after an incubation period of 48 h. When B lymphocytes were preactivated in vitro with Staphylococcus aureus Cowan strain I (SAC), neither LTB4 nor LTC4 was able to promote proliferation and/or IgG and IgM secretion. In contrast, when resting B lymphocytes were stimulated with a suboptimal concentration (3 U/ml) of IL-4, LTB4, but not LTC4, potentiated both the Fc epsilon RII/CD23 and the class II MHC antigen expression, and the release of soluble CD23 in a dose-dependent manner, without affecting the kinetics of these responses. Furthermore, LTB4, but not LTC4, amplified both the proliferative response and the IgG and IgM secretion induced by addition of a suboptimal dose of IL-4 (3 U/ml) to SAC-preactivated B lymphocytes. Again, LTB4 did not modify the kinetics of the proliferative response promoted by IL-4. Although LTB4 potentiated IL-4-induced IgG and IgM secretion from SAC-activated B lymphocytes, no production of IgE was observed. These data indicate that LTB4 could play a regulatory role in the modulation of IL-4-induced signaling in human B lymphocytes. 相似文献
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The aim of the present work was to study regulatory interactions between MHC class I molecules and the interleukin (IL)-2, IL-3, and IL-4 receptors and functional interactions between the receptors for IL-2 and IL-4. Our major observations were: (1) quiescent splenic T cells exposed to specific anti-MHC class I antibodies become responsive to IL-2 and IL-4 stimulation; (2) T-cell clones (CTLL-2 and HT-1) grown at high cell density or low IL-2 concentrations become refractory to IL-2 and IL-4 stimulation. After exposure to anti-class I antibodies the refractory cells recover responsiveness to lymphokine-induced proliferation; (3) IL-2 receptor expression is non-inducible in class I-negative T-lymphoma cells, but is inducible following class I gene transfection of the cells; (4) exposure of T-cells and clones to IL-2 receptor antibody increases the responsiveness to IL-4 stimulation; (5) IL-2 and IL-4 act synergistically at low and substimulatory lymphokine levels; and (6) IL-3 responsiveness of hemopoietic cells is not influenced by exposure to anti-MHC class I antibody. It is concluded that class I molecules are of importance for the functional expression of the receptors for IL-2 and IL-4 and that these receptors are functionally interrelated. 相似文献
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Hastings KT Lackman RL Cresswell P 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(12):8569-8577
Ag processing and presentation via MHC class II is essential for activation of CD4(+) T lymphocytes. gamma-IFN-inducible lysosomal thiol reductase (GILT) is present in the MHC class II loading compartment and has been shown to facilitate class II Ag processing and recall responses to Ags containing disulfide bonds such as hen egg lysozyme (HEL). Reduction of proteins within the MHC class II loading compartment is hypothesized to expose residues for class II binding and protease trimming. In vitro analysis has shown that the active site of GILT involves Cys(46) and Cys(49), present in a CXXC motif that shares similarity with the thioredoxin family. To define the functional requirements for GILT in MHC class II Ag processing, a GILT-deficient murine B cell lymphoma line was generated and stably transduced with wild-type and cysteine mutants of GILT. Intracellular flow cytometric, immunoblotting, and immunofluorescence analyses demonstrated that wild-type and mutant GILT were expressed and maintained lysosomal localization. Transduction with wild-type GILT reconstituted MHC class II processing of a GILT-dependent HEL epitope. Mutation of either Cys(46) or Cys(49) abrogated MHC class II processing of a GILT-dependent HEL epitope. In addition, biochemical analysis of these mutants suggested that the active site facilitates processing of precursor GILT to the mature form. Precursor forms of GILT-bearing mutations in Cys(200) or Cys(211), previously found to display thiol reductase activity in vitro, could not mediate Ag processing. These studies demonstrate that the thiol reductase activity of GILT is its essential function in MHC class II-restricted Ag processing. 相似文献
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Induction of class I and class II MHC antigen expression on murine bone marrow-derived macrophages by IL-4 (B cell stimulatory factor 1) 总被引:6,自引:0,他引:6
P M Stuart A Zlotnik J G Woodward 《Journal of immunology (Baltimore, Md. : 1950)》1988,140(5):1542-1547
We have studied the effects of IL-4 (B cell stimulatory factor 1) on the expression of MHC gene products in normal bone marrow-derived macrophages, peritoneal macrophages, and the myelomonocytic cell line WEHI-3. Using both IL-4-containing T cell supernatant and rIL-4, we have observed significant induction of both class I and class II MHC surface expression (about 1.5- to 4-fold increase) in 2-, 3-, and 4-day cultures of bone marrow-derived macrophages. This induction was also apparent at the mRNA level as assessed by Northern blot analysis using A beta, E alpha, and class I probes. Kinetic analysis revealed that induction of class II mRNA by IL-4 was slower than induction by IFN-gamma, requiring 48 h before a significant increase was noted. The magnitude of MHC induction by IL-4 was not as great as that seen with IFN-gamma, which was found to increase surface expression of MHC antigens two- to eightfold. IL-4 also differs from IFN-gamma in the repertoire of macrophages responsive to it. IL-4 was unable to induce class I or class II expression in either thioglycolate-elicited peritoneal macrophages or WEHI-3 cells whereas IFN-gamma induced MHC antigen expression on both cell types under the same conditions. These data demonstrate that IL-4 is capable of inducing both class I and class II MHC gene products in some, but not all, macrophages. 相似文献
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Mukherjee P Dani A Bhatia S Singh N Rudensky AY George A Bal V Mayor S Rath S 《Journal of immunology (Baltimore, Md. : 1950)》2001,167(5):2632-2641
Peptides from extracellular proteins presented on MHC class II are mostly generated and loaded in endolysosomal compartments, but the major pathways responsible for loading peptides from APC-endogenous sources on MHC class II are as yet unclear. In this study, we show that MHC class II molecules present peptides from proteins such as OVA or conalbumin introduced into the cytoplasm by hyperosmotic pinosome lysis, with efficiencies comparable to their presentation via extracellular fluid-phase endocytosis. This cytosolic presentation pathway is sensitive to proteasomal inhibitors, whereas the presentation of exogenous Ags taken up by endocytosis is not. Inhibitors of nonproteasomal cytosolic proteases can also inhibit MHC class II-restricted presentation of cytosolically delivered protein, without inhibiting MHC class I-restricted presentation from the same protein. Cytosolic processing of a soluble fusion protein containing the peptide epitope I-Ealpha(52-68) yields an epitope that is similar to the one generated during constitutive presentation of I-Ealpha as an endogenous transmembrane protein, but is subtly different from the one generated in the exogenous pathway. Constitutive MHC class II-mediated presentation of the endogenous transmembrane protein I-Ealpha is also specifically inhibited over time by inhibitors of cytosolic proteolysis. Thus, Ag processing in the cytoplasm appears to be essential for the efficient presentation of endogenous proteins, even transmembrane ones, on MHC class II, and the proteolytic pathways involved may differ from those used for MHC class I-mediated presentation. 相似文献
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Kobayashi H Nagato T Aoki N Sato K Kimura S Tateno M Celis E 《Cancer immunology, immunotherapy : CII》2006,55(7):850-860
The product of Wilms‘ tumor gene 1 (WT1) is overexpressed in diverse human tumors, including leukemia, lung and breast cancer,
and is often recognized by antibodies in the sera of patients with leukemia. Since WT1 encodes MHC class I-restricted peptides
recognized by cytotoxic T lymphocytes (CTL), WT1 has been considered as a promising tumor-associated antigen (TAA) for developing
anticancer immunotherapy. In order to carry out an effective peptide-based cancer immunotherapy, MHC class II-restricted epitope
peptides that elicit anti-tumor CD4+ helper T lymphocytes (HTL) will be needed. In this study, we analyzed HTL responses against WT1 antigen using HTL lines elicited
by in vitro immunization of human lymphocytes with synthetic peptides predicted to serve as HTL epitopes derived from the
sequence of WT1. Two peptides, WT1124–138 and WT1247–261, were shown to induce peptide-specific HTL, which were restricted by frequently expressed HLA class II alleles. Here, we
also demonstrate that both peptides-reactive HTL lines were capable of recognizing naturally processed antigens presented
by dendritic cells pulsed with tumor lysates or directly by WT1+ tumor cells that express MHC class II molecules. Interestingly,
the two WT1 HTL epitopes described here are closely situated to known MHC class I-restricted CTL epitopes, raising the possibility
of stimulating CTL and HTL responses using a relatively small synthetic peptide vaccine. Because HTL responses to TAA are
known to be important for promoting long-lasting anti-tumor CTL responses, the newly described WT1 T-helper epitopes could
provide a useful tool for designing powerful vaccines against WT1-expressing tumors. 相似文献
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Differential antigen-presenting cell requirements of hapten-specific T cell lines restricted to class II determinants 总被引:1,自引:0,他引:1
J H Hanke R G Cook L A Lopez R R Rich 《Journal of immunology (Baltimore, Md. : 1950)》1987,138(8):2384-2391
We used a panel of class II-restricted T cell lines (TCL), generated against trinitrophenyl (TNP)-modified autologous peripheral blood mononuclear cells (PBMC), to examine the antigen-presenting functions of various PBMC-derived class II-positive cell types, including adherent cells, B + null cells, and activated T cells. However, activated T cells and transformed or activated B cells differed in their ability to present TNP to the TCL; TNP-modified activated lymphocytes stimulated only a subset of the class II-restricted TCL that responded to class II-positive resting cells. Moreover, certain antigen-specific TCL distinguished between antigen presented on activated T cells and transformed B cells. The differences in stimulatory capacity for particular TCL did not appear to reflect differences in the expression of class II molecules or in the ability of these cells to deliver hormonal signals or process antigen. Instead, the data suggest that differences in the ability of the cells to recognize antigen on the surface of different class II-positive cells may be a function of a secondary cell surface interaction. 相似文献
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Regulation of Fc receptor for IgE (CD23) and class II MHC antigen expression on Burkitt's lymphoma cell lines by human IL-4 and IFN-gamma 总被引:10,自引:0,他引:10
F Rousset R W Malefijt B Slierendregt J P Aubry J Y Bonnefoy T Defrance J Banchereau J E de Vries 《Journal of immunology (Baltimore, Md. : 1950)》1988,140(8):2625-2632
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L T Clement T F Tedder G L Gartland 《Journal of immunology (Baltimore, Md. : 1950)》1986,136(7):2375-2381
Although class II antigens encoded by genes in the major histocompatibility complex (MHC) are important as recognition structures for immunoregulatory cell interactions, the precise functional role of these molecules in the biological responses of B lymphocytes is unknown. In the studies described here, we have examined the effects of six monoclonal antibodies reactive with human class II MHC antigens on B cell activation and proliferation. Peripheral blood IgM+ B cells purified by fluorescence-activated cell sorter (FACS) techniques were stimulated with anti-mu antibodies, protein A-bearing Staphylococcus aureus (SAC), or in T cell-dependent activation cultures. The B cell proliferative responses induced by these stimuli were inhibited 68 to 90% by low concentrations (1 to 5 micrograms/ml) of antibodies reactive with class II MHC antigens. Antibodies specific for DR and DQ antigens were both effective inhibitors of B cell proliferation. This inhibition was not due to the binding of antibody to B cell Fc-IgG receptors, because IgM and IgG anti-class II antibodies were equally potent as inhibitors. When responses of B cells fractionated on the basis of cell size by forward angle light scatter were analyzed, anti-DR and anti-DQ antibodies inhibited the proliferation of small, resting IgM+ cells induced by T-independent as well as T-dependent stimuli. Activation-dependent increases in B cell size and RNA synthesis were similarly inhibited. In contrast, the responses of large B cells (that had been preactivated in vivo) to T cell-derived B cell growth factors were not affected by anti-class II antibodies. These data suggest that class II MHC molecules do not serve merely as cellular interaction structures but also directly participate in early events of the B cell activation cascade that precede cell enlargement or increased RNA synthesis. After activation and expression of receptors for growth factors, however, B cell class II MHC antigens no longer mediate signals required for mitogenesis. 相似文献
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HLA-DM catalyzes the exchange and selection of ligands for MHC class II molecules within mature endosomal/lysosomal compartments. Here, evidence is provided that DM edits peptides in early endosomes, thus influencing presentation via recycling class II molecules. Maximal class II-restricted presentation of an albumin-derived peptide, dependent on endocytosis and recycling class II molecules, was observed in cells lacking HLA-DM. DM editing of this epitope was observed in early endocytic compartments as shown using inhibitors of early to late endosomal transport. Editing was tempered by coexpression of HLA-DO, suggesting that DM:DO ratio may be important in guiding epitope editing in early endosomal compartments. Thus, HLA-DM appears to interact with, and edit epitopes displayed by, recycling class II molecules. 相似文献