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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The predominant immunoregulatory activity of alveolar macrophages (AM) on T lymphocytes is to suppress their responses to antigenic and mitogenic stimuli. The suppressive activity of human AM for T cell responses to phytohemagglutinin (PHA) was further characterized. At ratios of AM to T lymphocytes of 0.4:1 to 1.6:1, AM inhibited the blastogenic response (3H-thymidine uptake into DNA) to PHA by 26 to 87%, respectively. Blood monocytes precultured in vitro for 5 to 7 days inhibited responses to PHA similarly. Freshly isolated blood monocytes, peritoneal macrophages, and A-549 epithelial and CCD-18Lu fibroblast cell lines failed to inhibit T lymphocyte responses. AM were capable of suppressing PHA-induced blastogenesis of purified CD4 cells without the addition of other cells. Cell contact was required for suppression of CD4 cells, as demonstrated using dual chambers. T cells precultured with AM with or without PHA retained the ability to respond to PHA compared with control T cells not precultured with AM. Kinetic experiments showed that AM needed to be added at the initiation of a 3-day culture period for suppression to occur. Analysis of the T cell DNA cycle revealed that AM decreased the percentage of cells entering the synthesis phase of DNA production. Flow cytometry also was used to assess the effect of AM on early markers of T cell activation. AM inhibited the percentage of T cells expressing the interleukin-2 receptor 46 to 83% and the transferrin receptor 58 to 78% at 24 to 48 h after stimulation with PHA. There was no effect of AM on expression of HLA-DR.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1993 Jan
PMID:Characterization of suppressor function of human alveolar macrophages for T lymphocyte responses to phytohemagglutinin: cellular selectivity, reversibility, and early events in T cell activation. 809 42

Treatment of patients with anti-CD4 mAbs induces both functional alterations of CD4+ cells and depletion of circulating CD4+ lymphocytes. Some of these effects depend on the amount of mAb molecules bound per CD4+ cell and on the properties of the Fc part of the mAb (isotype specificity). We have investigated the fate of anti-CD4 monoclonal antibodies (mAbs) after their interaction with CD4 protein on the surface of peripheral blood lymphocytes (PBL). We used seven anti-CD4 mAbs whose epitope specificity, equilibrium constant and kinetics of binding are reported. Lymphocytes were saturated with anti-CD4 mAbs either at +4 degrees C or 37 degrees C then washed and incubated in antibody-free medium. At different time intervals cells were processed for analysis. By indirect immunofluorescence, it was shown that the amount of surface-bound mAb decreased rapidly when cells were incubated at 37 degrees C, but not at 4 degrees C. With 125I-mAbs, we demonstrate that there was a rapid internalization of the molecules followed by the re-expression on the cell surface of a part of initially bound mAbs and by the release of partially degraded antibody in the cell supernatant. In the presence of sodium azide (10 mM) only a slow dissociation of intact antibody occurred, without internalization. The radioactive material eluted in the 100-200 kDa zone from supernatants was only partly adsorbed on protein A and hardly on CD4+ cells, indicating that alterations of the Fc region and loss of antigen binding activity, possibly by formation of CD4-anti-CD4 complexes, had occurred during the process of internalization and release into the extracellular medium. These data may be important to consider for adjusting the dosage of anti-CD4 mAbs to be administered.
Mol Immunol 1993 May
PMID:Internalization and degradation of anti-CD4 monoclonal antibodies bound to human peripheral blood lymphocytes. 809 32

The mechanism of antiviral activity of the CD4-derived peptide 75-99 was compared with that of sulfated polysaccharides. A set of peptides representing all the high positive charge density regions of gp120 and gp41 was used to determine whether electrostatic interactions occur between these negatively charged agents and positively charged HIV envelope fragments. Synthetic peptide AZ2, amino acids 75-99 from V1 CD4, KIEDSDTYIC(Acm)-EVEDQKEEVQLLVFG, and dextran sulfate 500,000 (DS 500) were used as inhibitory agents of antibody binding in ELISA using: (1) anti-peptide rabbit antibodies; (2) sera from HIV infected persons. Peptide AZ2 and DS were both shown to block antibody binding to peptide (301-323) from the principal neutralizing domain (PND) and peptide (495-516) from the gp120 C-terminus. The blocking concns were 1-2 micrograms/ml for DS and 125-250 micrograms/ml for AZ2. The ELISA system based on rabbit anti-peptide antibodies was less sensitive than that based on positive human sera. Chemical modification of lysine epsilon-amino groups of these peptides resulted in complete failure to bind either DS or AZ2. A correlation was found between the inhibitory activities of a number of sulfated polysaccharides in a syncytium formation assay and in peptide ELISA. The mechanism of direct interactions of specific regions of gp120 with the CDR3-like region of CD4 is proposed.
Mol Immunol 1993 Aug
PMID:CD4-derived peptide and sulfated polysaccharides have similar mechanisms of anti-HIV activity based on electrostatic interactions with positively charged gp120 fragments. 810 73

Ganglioside (GM1) modulation of CD4 off the surface of T lymphocytes defined functions of the CD4 molecule during signal transduction through the T cell receptor (TCR)/CD3 complex. Antibody cross-linking of CD3 alone (3 x 3) stimulated phospholipase C (PLC) activity, rapid Ca2+ flux, and protein phosphorylations in freshly isolated human T lymphocytes. Antibody cross-linking of CD4 and CD3 (3 x 4) stimulated greater signaling than that caused by 3 x 3. Cross-linking CD4 alone did not stimulate these signaling processes. GM1-modulation of CD4 from the cell surface blocked all aspects of the augmented signaling imparted by CD4 co-modulation with CD3. In comparison, pretreatment with the protein tyrosine kinase inhibitor genistein inhibited 3 x 4-stimulated PLC activity and protein phosphorylation but not Ca2+ flux. Antibody cross-linking of the tyrosine phosphatase CD45 with 3 x 4 (3 x 4 x 45) also inhibited CD4-augmented phosphorylations and like genistein did not reduce Ca2+ levels. In conclusion, these data demonstrate that CD4 can augment signal transduction through the TCR/CD3 complex by its physical proximity to CD3. TCR/CD3-signaling augmentation by CD4 stimulated protein tyrosine kinases and PLC activities but stimulated intracellular Ca2+ flux through an independent mechanism(s).
Cell Mol Biol Res 1993
PMID:Ganglioside (GM1) distinguishes the effects of CD4 on signal transduction through the TCR/CD3 complex in human lymphocytes. 810 89

The human immunodeficiency virus type 1 (HIV-1) encoded Vpu is a small integral membrane phosphoprotein that functions in the enhancement of viral particle release and has more recently been shown to cause degradation of CD4 at the endoplasmic reticulum. We have demonstrated earlier that Vpu is phosphorylated by the ubiquitous casein kinase-2 (CK-2) in HIV-1 infected cells. The phosphoacceptor sites targeted by CK-2 in Vpu, however, have not been demonstrated and it was unclear whether Vpu was phosphorylated at one or more of its four serine residues. In this study we characterized the CK-2 phosphoacceptor sites in Vpu using recombinant CK-2 for in vitro phosphorylation of recombinant Vpu protein as well as synthetic peptides of Vpu. Phosphorylation of both Ser52 and Ser56 was demonstrated by in vitro phosphorylation using three 54-residue peptides comprising the entire hydrophilic part of Vpu and containing single serine to asparagine transitions in either position 52 or 56. The Km values of CK-2 to these peptides were established, revealing a preferential phosphorylation of Ser56. The Km values are: Ser56 = 31 microM; Ser 52 = 156 microM; wild type = 27 microM. In addition, we studied phosphorylation of Vpu by endogenous CK-2 following in vitro translation in rabbit reticulocyte lysate of wild-type Vpu or a mutant, Vpum2/6, carrying serine to asparagine changes at amino acid positions 52 and 56. The in vivo phosphorylation of Vpu was studied in transiently transfected human embryonic kidney (293) cells. In this system, the mutant Vpum2/6 was not phosphorylated, indicating that the seryl residues of Vpu at amino acid positions 52 and 56, but not those at positions 23 and 61, are phosphorylated by CK-2. The two CK-2 phosphorylation sites are conserved in all known Vpu sequences and represent the consensus Ser52GlyAsn(Glu/Asp)Ser(Glu/Asp)Gly(Glu/Asp)59. Prediction of the secondary structure revealed a conserved alpha-helix-turn-alpha-helix motif for the hydrophilic C-terminal part of Vpu. A structural model for Vpu is proposed in which the membrane anchor precedes a region comprising two amphipathic alpha-helices of opposed polarity, joined by a strongly acidic turn that protrudes into the cytoplasm and contains the CK-2 phosphorylation sites. Possible functional and structural homologies of Vpu to the membrane channel-forming M2 protein of influenza A viruses are discussed.
J Mol Biol 1994 Feb 11
PMID:The human immunodeficiency virus type 1 encoded Vpu protein is phosphorylated by casein kinase-2 (CK-2) at positions Ser52 and Ser56 within a predicted alpha-helix-turn-alpha-helix-motif. 810 1

The phosphorylation and dephosphorylation of proteins on tyrosyl residues are key regulatory mechanisms in T-cell signal transduction and are controlled by the opposing activities of protein tyrosine kinases and phosphotyrosyl phosphatases (PTPs). In T cells, several nontransmembrane protein tyrosine kinases are associated with receptors; for example, Lck is bound to the coreceptors CD4 and CD8 and becomes activated upon their stimulation. In comparison, little is known about the role of nontransmembrane PTPs in early T-cell signaling. SH-PTP1 (PTP1C, HCP, SHP) is a nontransmembrane PTP expressed primarily in hematopoietic cells, including T cells. We have found that SH-PTP1 is basally phosphorylated on serine in resting T cells. Upon stimulation of CD4 or CD8 either in a T-cell hybridoma cell line or in primary thymocytes, SH-PTP1 becomes tyrosyl phosphorylated. Moreover, SH-PTP1 is constitutively phosphorylated on tyrosine in the Lck-overexpressing lymphoma cell line LSTRA. SH-PTP1 is also a good substrate for recombinant Lck in vitro. Comparisons of the tryptic phosphopeptide maps of wild-type SH-PTP1 and deletion and point mutations establish that the two sites (Y-536 and Y-564) which are directly phosphorylated by Lck in vitro are also phosphorylated in vivo in LSTRA cells. One of these sites (Y-564) is phosphorylated in T cells in response to Lck activation. We conclude that SH-PTP1 undergoes Lck-dependent tyrosyl phosphorylation in T cells and likely plays a role in early T-cell signaling.
Mol Cell Biol 1994 Mar
PMID:Lck-dependent tyrosyl phosphorylation of the phosphotyrosine phosphatase SH-PTP1 in murine T cells. 811 15

The tyrosine protein kinase p56lck transduces signals important for antigen-induced T-cell activation. In transgenic mice, p56lck is oncogenic when overexpressed or expressed as a mutant, catalytically activated enzyme. In humans, the LCK gene is located at the breakpoint of the t(1;7)(p34;q34) chromosomal translocation. This translocation positions the beta T-cell receptor constant region enhancer upstream of the LCK gene without interrupting the LCK coding sequences, and a translocation of this sort occurs in both the HSB2 and the SUP-T-12 T-cell lines. We have found that, although the level of the p56lck protein in HSB2 cells is elevated approximately 2-fold in comparison with that in normal T-cell lines, total cellular tyrosine protein phosphorylation is elevated approximately 10-fold. Increased levels of phosphotyrosine in HSB2 cells resulted from mutations in the LCK gene that activated its function as a phosphotransferase and converted it into a dominant transforming oncogene. The oncogenic p56lck in HSB2 cells contained one amino acid substitution within the CD4/CD8-binding domain, two substitutions in the kinase domain, and an insertion of Gln-Lys-Pro (QKP) between the SH2 and kinase domains. In NIH 3T3 fibroblasts, three of these mutations cooperated to produce the fully oncogenic form of this p56lck variant. These results suggest that mutation of LCK may contribute to some human T-cell leukemias.
Mol Cell Biol 1994 Apr
PMID:Oncogenic activation of the Lck protein accompanies translocation of the LCK gene in the human HSB2 T-cell leukemia. 813 46

Repeated injections of mitomycin C-treated T2 fibrosarcoma cells into tumor-sensitized mice cause regression of a secondary tumor graft and more than 90% of the mice are cured. In the data presented here, an enhancement of the cytolytic cell-mediated activities measured in vitro against the specific T2 targets is shown in lymph nodes draining the tumor and in the spleen during the process of tumor rejection. Histopathologic studies revealed a rapid and marked accumulation of mononuclear cells mostly at the periphery of the rejected tumor tissue. A significant increase of CD8-positive, asialo GM1-positive and acid phosphatase-positive cells was observed in the rejected tumors whereas CD4-positive cells were similarly detected in both progressing and rejected tumor tissue. As macrophages seemed to be the population presenting the most persistent variation after immunization, the production of TNF-alpha was studied within the tumor site and in the lymphoid tissues during the regression process. Firstly, the presence of TNF-alpha within the cytoplasm of most of the adherent cell fractions isolated from the spleen and the tumor of immune mice was demonstrated by immunocytochemistry. Next, TNF-alpha mRNA-containing cells were determined by in situ hybridization of frozen tumor sections and identified essentially as tumor infiltrating macrophages. Finally, the macrophage populations isolated from tumors and from the spleen of immune mice were able to produce in vitro large quantities of TNF-alpha without exogenous stimulation. These findings support the role of TNF-alpha in the effector mechanisms contributing to the tumor regression process.
Virchows Arch B Cell Pathol Incl Mol Pathol 1993
PMID:Phenotypical and functional analyses of mononuclear cells during rejection of a transplanted murine fibrosarcoma. 814 54

The V2 region of simian immunodeficiency virus (SIV) and V3 region of human immunodeficiency virus type 1 (HIV-1) have been reported to be neutralization epitopes. We analysed the corresponding regions in HIV-2. Synthetic peptides modeling the V2 (aa 149-168) and V3 (CV3: aa 298-315 and NV3: aa 306-324) regions of the HIV-2 external envelope glycoprotein were coupled to KLH and used as immunogens in rabbits. We characterized the resulting antiV2 and antiV3 antibodies for their ability to recognize native and deglycosylated HIV-2 envelope glycoprotein, to block gp-CD4 interaction and to inhibit syncytium formation in vitro. The three synthetic peptides induced antibodies able to recognize specifically the native HIV-2 envelope glycoprotein with a significant avidity (K0.5 between 6 x 10(-7) and 8 x 10(-9) M). Interestingly, the reactivity of antibodies produced against the V2 peptide, which contains two potential sites of N-glycosylation, was higher against the fully deglycosylated than glycosylated HIV-2 external envelope glycoprotein (gp105). The antipeptide antibodies were used to investigate the topography of these regions in the preformed gp-CD4 complex in indirect immunofluorescence assays. The V2 and V3 regions in the complex remained accessible to their respective antibodies. Moreover, preincubation of gp105 with anti V2 or anti V3 antibodies did not prevent gp-CD4 interaction. Thus the V2 and V3 regions are not directly involved in the gp105 binding site for the CD4 receptor. Finally, in contrast with results obtained with antibodies produced against the V3 region of HIV-1 gp120 and monoclonal antibodies produced against the V3 of SIV, antibodies produced against V2 and V3 of HIV-2 were unable to inhibit syncytium formation induced by HIV-2 in vitro.
Mol Immunol 1994 Apr
PMID:Specificity of antipeptide antibodies produced against V2 and V3 regions of the external envelope of human immunodeficiency virus type 2. 815 39

The membrane-spanning and cytoplasmic domains of CD4 and CD8 were replaced by those of TGN38. After transient expression in HeLa cells, the location of the hybrid proteins was determined using immunofluorescence and quantitative immuno-electron microscopy, FACS analysis and metabolic labeling. The membrane-spanning domain was found to contain a signal that localized hybrid proteins to the TGN. This was in addition to the signal previously identified in the cytoplasmic domain (Bos, K., C. Wraight, and K. Stanley. 1993. EMBO (Eur. Mol. Biol. Organ) J. 12:2219-2228. Humphrey, J. S., P. J. Peters, L. C. Yuan, and J. S. Bonifacino. 1993. J. Cell Biol. 120:1123-1135. Wong, S. H., and W. Hong. 1993. J. Biol. Chem. 268:22853-22862). The different properties of these two signals suggest that each operates by a different mechanism.
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PMID:The TGN38 glycoprotein contains two non-overlapping signals that mediate localization to the trans-Golgi network. 816 44


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