摘要:

AbstractProstaglandin E2(PGE2) favors T helper type 2 (Th2)‐like cytokine secretion profiles in murine and human CD4+T cells by inhibiting the production of the Th1‐associated cytokines interleukin‐2 (IL‐2) and interferon‐γ (IFN‐γ) and up‐regulating the production of the Th2‐associated cytokines IL‐4 and IL‐5 in a dose‐dependent way. However, the potent inhibition of IL‐2 production by PGE2seems to be in contrast with the simultaneous up‐regulation of IL‐4 and IL‐5 production, because the induction of these cytokines requires IL‐2. We, therefore, investigated to which extent the net modulatory effect of PGE2is determined by the availability of IL‐2. To this aim, we examined the effects of PGE2on the cytokine secretion profiles of a panel of human Th0 clones upon stimulation via different activation pathways, resulting either in high or low IL‐2 production. The differential modulation of Th1 and Th2 cytokines by PGE2was observed only upon modes of stimulation resulting in high IL‐2 production. When IL‐2 production was low, PGE2inhibited the secretion of all four cytokines. These different modulation patterns were directly related to the IL‐2 availability, because (i) neutralizing antibody to IL‐2 abrogated the up‐regulatory effect of PGE2on IL‐4 and IL‐5 secretion in experiments with high endogenous IL‐2 levels, (ii) lack of differential cytokine modulation by PGE2in conditions with low levels of endogenous IL‐2 could be restored with exogenous IL‐2, and (iii) cell viability was comparable in all conditions. These results demonstrate that the net modulatory effect of PGE2on the cytokine secretion profile of T cells critically depends on the availability of IL‐2. Since this parameter varies with the experimental conditions and the T cell population studied, this finding may explain why certain immune responses may be eit

ISSN:0014-2980    

DOI:10.1002/eji.1830250112

出版商:WILEY‐VCH Verlag GmbH    

年代:1995

数据来源: WILEY

摘要:

AbstractThe activities of six synthetic CC chemokines, MCP‐1, MCP‐2, MCP‐3, RANTES, MIP‐1α and MIP‐1β on human blood monocytes were studied. All CC chemokines elicited a bimodal migration responsein vitro. Highest numbers of migrating cells were obtained with the monocyte chemotactic proteins (MCP) and RANTES, somewhat lower numbers with MIP‐1α, and only weak migration with MIP‐1β. The most potent attractants were MCP‐1 and MIP‐1α which reached maximum efficacy at 0.1 to 1 nM. All CC chemokines also induced the release of N‐acetyl‐β‐D‐glucosaminidase from cytochalasin B‐pretreated monocytes. The MCP were most effective (MCP‐1>MCP‐3>MCP‐2), RANTES and MIP‐1α showed moderate (1/3 of MCP‐1 activity), and MIP‐1β only minimal activity. Cytosolic free Ca2+changes and exocytosis were used to monitor receptor desensitization. Marked cross‐desensitization was observed among MCP‐1, MCP‐2 and MCP‐3 on the one hand, and RANTES, MIP‐1α and MIP‐1β on the other, indicating receptor sharing within these two subgroups of CC chemokines. The responses to RANTES, MIP‐1α and MIP‐1β were also moderately to markedly desensitized by pretreatment with MCP‐1, MCP‐2 or MCP‐3, while the responses to the MCP were virtually unaffected by pretreatment with RANTES, MIP‐1α and MIP‐1β. These results suggest that the MCP also interact with receptors recognized by RANTES, MIP‐1α and MIP‐1β, but not vice versa. Binding studies were performed with radiolabeled MCP‐1 or MIP‐1α. All MCP competed readily for labeled MCP‐1 yielding a concentration‐dependent sigmoidal displacement curve. Displacement with RANTES, MIP‐1α and MIP‐1β was observed at higher concentrations, but was not complete. Radiolabeled MIP‐1α was displaced efficiently by MIP‐1α or MIP‐1β, but only partially by RANTES. Of the

ISSN:0014-2980    

DOI:10.1002/eji.1830250113

出版商:WILEY‐VCH Verlag GmbH    

年代:1995

数据来源: WILEY

摘要:

AbstractStudies of experimental autoimmune encephalomyelitis (EAE) in rodents have revealed that encephalitogenic T cell lines reactive with myelin basic protein (BP) are frequently dominated by clones expressing a restricted T cell receptor repertoire. Using the rat EAE model, we have begun to examine the basis for clonal dominance within BP‐reactive T cell lines. We find that variations introduced into the standard protocol of periodic antigen stimulation produce marked shifts in the representation of different clones within encephalitogenic T cell populations. For example, altering the source of antigen‐presenting cells (APC), while holding antigen (BP) constant, and substituting BP from guinea pig (GPBP) for that of the rat antigen (RBP) with constant APC, both cause shifts in the composition of the dominant clones within BP‐reactive T cell lines. Our results suggest that: (i) adherence to an invariant protocol of antigen challenge may lead to an underestimation of the diversity of BP‐reactive encephalitogenic T cell populations; and (ii) the minor structural differences between GPBP and RBP not only cause the weak immunogenicity of RBP but also result in the alteration of different T cell subsets. These observations indicate that apparent restrictions upon the repertoire of autoimmune T cells should be interpreted with caution when such cells are elicited by immunization with foreign a

ISSN:0014-2980    

DOI:10.1002/eji.1830250114

出版商:WILEY‐VCH Verlag GmbH    

年代:1995

数据来源: WILEY

摘要:

AbstractPrevious studies have demonstrated tumor‐ and allo‐specific cytotoxic γδ T lymphocytes in rats. In this report we define the surface phenotype of these T cell receptor (TCR)γδ+T cells and demonstrate distinct CD45 mRNA splicing in activated γδ cytotoxic T lymphocytes (CTL). γδ T lymphocytes in the blood and the peritoneal cavity were TCRαβ−‐CD3+CD8α+CD45RC+but expressed variable levels of LFA‐1 molecules. Normal peritoneal γδ T lymphocytes, peritoneal γδ T cells from rats injected with the bacterial superantigen staphylococcal enterotoxin A (SEA) as well as γδ T lymphocytes in peripheral blood were all LFA‐1low, Peritoneal γδ T cells from tumor‐, and allo‐sensitized rats were either LFA‐1lowor LFA‐1highand specific cytotoxicity was highly enriched in the LFA‐1highsubset. No cytolytic activity against SEA‐presenting cells was recorded in γδ T cells from SEA‐injected rats. Different isoforms of CD45 in T cells are generated by alternative mRNA splicing of exons 4, 5, 6 (or A, B and C, respectively) and the recently described alternate exon 7. CD45 splicing in sorted γδ T cells was evaluated utilizing reverse transcription polymerase chain reaction. Normal peritoneal γδ T cells expressed exon(578), exon(678), exon(78) and the extensively spliced exon(8) variant. Peritonealγδ T cells from rats sensitized with irradiated syngeneic tumor cells, allogeneic cells or bacterial superantigen SEA as well as γδ T lymphocytes in peripheral blood contained the full‐length exon(45678), as well as the exon(5678), exon(578), exon(678) and exon(78) splicing products. Notably, the exon(8) variant was also seen in peritoneal γδ T cells of SEA‐sensitized rats. Sorted tumor‐specific LFA‐1highγγ CTL expressed exon(45678), exon(5678), exon(578), exon(678) and exon(78) CD45 splicing products whereas the non‐cytolytic LFA‐1lowγδ T cell subset also contained exon(8) variant. In summary, it is concluded that antigen‐specific TCRγδ+CTL express high levels of LFA‐1 and that the splicing machinery in these cytolytic cells favors expression of the exon(45678) and exon(5678) CD45 splicing products whereas the exon(8) variant is lost. TCRαβ+CTL express high levels of LFA‐1 but are devoid of the full‐length exon(45678) splicing product. The different CD45 splicing patterns found in αβ CTL and γδ CTL indicate different molecular requirement

ISSN:0014-2980    

DOI:10.1002/eji.1830250115

出版商:WILEY‐VCH Verlag GmbH    

年代:1995

数据来源: WILEY

摘要:

AbstractThe B cell activation molecule CD40 and the p55 tumor necrosis factor receptor (p55TNFR) belong to the same family of structurally conserved proteins. We constructed a chimeric receptor consisting of the CD40 extracellular and transmembrane domains and the p55TNFR intracellular domain. This receptor hybrid retained the biological activity and the ligand specificity of the respective wild‐type receptor domains. Thus it exerted a marked cytotoxic effect in three different transfected cell lines after activation not only with anti‐CD40 antibody but also with CD40 ligand (CD40L) in soluble and membrane‐bound forms. Using hybrid‐transfected baby hamster kidney cells we demonstrated that herpesvirus saimiri‐transformed human CD4+T lymphocytes constitutively express bioactive CD40 ligand on their surface. The hybrid receptor‐based assay was highly specific for CD40 activating reagents and more sensitive than an assay measuring CD40‐mediated B cell rescue from apoptosis. Hence CD40/p55TNFR transfectants may be useful for dissecting CD40L‐mediated events in T‐B cell interactions, and also to detect a defective CD40L molecule in putative hyper‐Ig

ISSN:0014-2980    

DOI:10.1002/eji.1830250116

出版商:WILEY‐VCH Verlag GmbH    

年代:1995

数据来源: WILEY

摘要:

AbstractWe reported that T cell receptor (TcR) γδ intestinal intraepithelial lymphocytes (i‐IEL) of host origin increased transiently, then decreased drastically at the early stage of non‐irradiated acute graft‐versus‐host disease (GVHD) in mice. We investigated the role of the TcR γδ i‐IEL of host origin in the pathogenesis of the intestinal lesions that occur during acute GVHD. The acute GVHD was induced in mice which had been depleted of TcR γδ byin vivoadministration of hamster monoclonal antibody (mAb) against TcR γδ. Although the degree of splenomegaly after the induction of acute GVHD in mice treated with anti‐TcR γδ mAb was similar to that in control mice treated with hamster anti‐2,4,6‐trinitrophenyl mAb, infiltration of donor‐derived T cells into the epithelium, and mitosis and apoptosis of crypt cells in the intestinal mucosa were dramatically suppressed in these mice. This suggest that host TcR γδ T cells in i‐IEL contribute to the development of en

ISSN:0014-2980    

DOI:10.1002/eji.1830250117

出版商:WILEY‐VCH Verlag GmbH    

年代:1995

数据来源: WILEY

摘要:

AbstractThe induction of contact sensitivity in mice by hapten reagents such as trinitrochlorobenzene (TNCB) involves the activation of class II major histocompatibility complex (MHC)‐restricted, hapten‐specific, CD4+T cells. Reports from different laboratories have indicated that the relevant antigenic epitopes in such reactions might include hapten‐conjugated, MHC class II‐associated peptides. This study for the first time directly demonstrates that hapten‐peptides account for the majority of determinants recognized by trinitrophenyl (TNP)‐specific CD4+T lymphocytes. The sequences of those TNP carrier peptides do not have to be related to mouse proteins. Thus, we show that TNP‐modified peptides derived from mouse IgG, pigeon cytochrome c or staphylococcal nuclease known to bind to I‐Abor from λ represser with specificity to I‐Adas well as TNP‐proteins such as bovine serum albumin, ovalbumin or keyhole limpet hemocyanin all create class II‐restricted hapten determinants for a number of TNP‐specific T cell clones and hybridomas. All of these cells were induced with cells modified by trinitrobenzene sulfonic acid (TNBS). In addition, we present arguments indicating that individual TNP‐specific helper T cells may cross‐react with different TNP‐peptides bound to identical class II molecules. Chemical treatment of antigen‐presenting cells with TNCB or TNBS may thus result in a limited number of particularly repetitive immunodominant hapten epitopes. Immunodominant epitopes were also indicated by an overrepresentation of the TCR elements Vβ2 and Vα10 in I‐Ab/TNP‐specific T cells. Most importantly, however, we demonstrate that TNP attached to lysine 97 in the staphylococcal nuclease peptide 93–105 (i.e.a clearly “non‐self” sequence) is able to prime mice for subsequent elicitation of contact sensitivity by TNCB in the absence of foreign protein. We take this to indicate that those TNP‐peptide determinants defined by us as immuno‐dominant are responsible f

ISSN:0014-2980    

DOI:10.1002/eji.1830250118

出版商:WILEY‐VCH Verlag GmbH    

年代:1995

数据来源: WILEY

摘要:

AbstractAn influence of cytotoxic T lymphocyte (CTL) response over Epstein‐Barr virus (EBV) evolution was first suggested by the finding that virus isolates from highly HLA‐A11‐positive Oriental populations were specifically mutated in two immunodominant A11‐restricted CTL epitopes. Here we turn to a second HLA allele, B35.01 and show that B35.01‐restricted CTL responses in Caucasian donors reproducibly map to a single peptide epitope, YPLHEQHGM, representing residues 458–466 of the type 1 EBV nuclear antigen 3 A protein (B95.8 strain). In this case, however, most EBV isolates from a highly B35.01‐positive population (in The Gambia) either retained the CTL epitope sequence or carried a mutation (P → S at position 2) which conserved antigenicity; changes leading to reduced antigenicity (Y → N at position 1) were found in only a minority of cases. Furthermore, CTL recognizing the YPLHEQHGM epitope could be reactivated from the blood of some B35.01‐positive Gambian donors byin vitrostimulation with the synthetic peptide, indicating that epitope‐specific immunity does exist in this population. Possible differences between the A11‐based and B35.01‐ba

ISSN:0014-2980    

DOI:10.1002/eji.1830250119

出版商:WILEY‐VCH Verlag GmbH    

年代:1995

数据来源: WILEY

摘要:

AbstractMinimal numbers of CD8+T cells are found in bronchoalveolar lavage (BAL) populations recovered from Sendai virus‐infected mice that are homozygous (−/−) for β2‐microglobulin (β2‐m) gene disruption. The prevalence of the CD8+set was substantially increased in the pneumonic lungs of 8−12‐week radiation chimeras made using substantially class I major histocompatibility complex (MHC) glycoprotein‐negative β2‐m (−/−) recipients and normal β2‐m (+/+) bone marrow. Even so, the CD8+(but not the CD4+) lymphocyte counts were still much lower than in the (+/+)→(+/+) controls. The (+/+)→(+/+) and (+/+)→(−/−) chimeras cleared Sendai virus and potent virus‐immune CD8+cytotoxic T lymphocytes (CTL) specific for H‐2Kb+ viral nucleoprotein peptide were found in the BAL from both groups. However, followingin vivodepletion of the CD4+population, only the (+/+)→(+/+) mice were able to deal with the infection. Similarly, adoptively transferred, H‐2Kb‐restricted CD8+T cells from previously‐primed (+/+) mice also failed to clear virus from the lungs of (+/+)→(−/−) chimeras infected within 2 weeks of reconstitution with bone marrow, though they were effective in the (+/+)→(+/+) controls. Sendai virus‐immune CD8+T cells are thus unable to eliminate virus‐infected β2‐m (−/−) lung epithelial cells that might be thought to be expressing very small amounts of either isolated class I heavy chain, or class I MHC glycoprotein that has bound β2‐m derived from β2‐m (+/+) T cells or macrophages present in the pneumonic lung. Furthermore, the CD8+CTL that are being exposed to β2‐m (+/+) stimulators in the BAL population can

ISSN:0014-2980    

DOI:10.1002/eji.1830250120

出版商:WILEY‐VCH Verlag GmbH    

年代:1995

数据来源: WILEY

摘要:

AbstractThe existence of a functional receptor for secretory component (SC) on the eosinophil membrane might explain the preferential degranulation induced by secretory IgA (sIgA) when compared to serum IgA. Indeed, flow cytometry analysis revealed that purified human SC could bind to a subpopulation (4–59%) of blood eosinophils purified from 19 patients with eosinophilia. Binding of radiolabeled human SC could be competitively inhibited using unlabeled SC or secretory IgA but not with serum IgA or IgG. Immunoprecipitation and immunosorbent chromatography using human SC revealed the presence of a major component at 15 kDa in eosinophil extracts as well as in culture supernatants but not in neutrophils. The 15‐kDa protein eluted from the human SC immunosorbent was able to bind to SC or to sIgA but not to serum IgA. Eosinophils preincubated with human SC or sIgA released eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO) after addition of anti‐SC or anti‐IgA monoclonal antibody as respective cross‐linking reagents. These results indicated that binding of free or complexed SC to human eosinophils could induce eosinophil degranulation. Furthermore, the dose‐dependent inhibition by SC of mediator release induced by sIgA but not by serum IgA, suggested that the receptor for SC could be involved in the preferential degranulation mediated by sIgA. These results indicate a novel pathway of eosinophil activation and its potential involvement in mucosal immunity, particularly in inflammatory diseases associated with infiltration of eosinophils and the enhanced product

ISSN:0014-2980    

DOI:10.1002/eji.1830250121

出版商:WILEY‐VCH Verlag GmbH    

年代:1995

数据来源: WILEY