摘要:

AbstractMice carrying thelprgene, SCG and MRL‐lpr/lprmice, were used to characterize the phenotype andlprgene of abnormally proliferating T cells in these mice. A major population which expanded in these mice were T cells expressing intermediate (int) levels of T cell receptor (TCR) (and CD3) and the phenotype of interleukin‐2 receptor (IL‐2R)βloα−(possibly abnormal TCRintcells). The levels of TCRhicells of thymic origin (generated through the mainstream of T cell differentiation in the thymus) profoundly decreased after the onset of disease. However, a small population of normal TCRintcells (i.e.IL‐2Rβhiα−) were also found to exist in all tested organs. For example, the majority of abnormal IL‐2RβloTCRintcells were CD4−8−CD2−, while normal IL‐2RβhiTCRintcells were a mixture of single‐positive cells (mainly CD8+), CD4−8−cells and CD2+cells. Moreover, normal TCRintcells preferentially produced normal Fas mRNA and Fas molecules from thelprgene. This phenomenon explains the leaky appearance of normal Fas mRNA and Fas molecules in mice carrying thelprgene. It is suggested that a small population of IL‐2RβhiTCRintcells are re

ISSN:0014-2980    

DOI:10.1002/eji.1830260702

出版商:WILEY‐VCH Verlag GmbH    

年代:1996

数据来源: WILEY

摘要:

AbstractEndothelial cell (EC) activation plays a key role in inflammation, thrombosis and organ rejection. Normally, EC are in a quiescent state in which their function is to prevent coagulation and thrombosis, and to participate in the regulation of leukocyte migration from the bloodstream into the tissue. Upon activation with cytokines or other stimuli, EC up‐regulate a number of genes, including E‐selectin (ELAM‐1), intercellular adhesion molecule (ICAM)‐1, vascular cell adhesion molecule (VCAM)‐1, interleukin (IL)‐1, IL‐8, tissue factor (TF), plasminogen activator inhibitor‐1 (PAI‐1), MCP‐1 (monocyte chemoattractant protein‐1) and endothelial cell inducible gene (ECI‐6). Arachidonic acid (AA) is produced by several cell types, including EC, and acts on various cells. We report here that AA inhibits the up‐regulation of some, but not all genes that are induced with EC activation in a dose‐dependent manner. AA suppresses TNF‐α, IL‐1α, LPS or PMA‐induced E‐selectin expression, as well as mRNA accumulation of E‐selectin, ICAM‐1 and IL‐8 stimulated by TNF‐α. The inhibition appears to be at the level of transcription. At the same time under the same conditions AA does not, repress mRNA accumulation for PAI‐1, ECI‐6, MCP‐1 and VCAM‐1. We suggest that the induced expression of AA with EC activation may result in

ISSN:0014-2980    

DOI:10.1002/eji.1830260703

出版商:WILEY‐VCH Verlag GmbH    

年代:1996

数据来源: WILEY

摘要:

AbstractMouse T cells co‐expressing an αβ T cell receptor (TCR) and the NK1.1 antigen have been shown to be major interleukin (IL)‐4‐producing cells and could therefore regulate cell‐mediated immune responses. We have identified a related subset of thymocytes co‐expressing a γδ TCR and NK1.1 which also produce IL‐4. Unlike αβ+NK1.1+thymocytes, the selection of γδ+NK1.1+thymocytes is not dependent upon β2‐microglobulin (β2m)‐associated class I molecule expression because these cells are present in β2m‐deficient mice. This suggests that γδ+NK1.1+T cells may regulate immune responses to a different variety of antigens. However, the development of αβ+NK1.1+and αβ+NK1.1+thymocytes appears to be related. Analysis of different mutant mice lacking αβ+NK1.1+thymocytes revealed a specific increase in γδ+NK1.1+thymocyte production when the block in αβ+NK1.1+thymocyte differen

ISSN:0014-2980    

DOI:10.1002/eji.1830260704

出版商:WILEY‐VCH Verlag GmbH    

年代:1996

数据来源: WILEY

摘要:

AbstractDespite the fact that the great majority of T cells at the site of an inflammatory response are not antigen specific, the mechanisms leading to activation and recruitment of these bystander T cells are poorly understood. We previously reported that soluble (s)CD23 potentiated the interleukin (IL)‐2‐induced interferon (IFN)‐γ production by T cells co‐cultured with autologous monocytes in the absence of T cell receptor (TCR) engagement. Our present data demonstrate that the IL‐2‐induced IFN‐γ secretion, in the presence but also in the absence of sCD23, is strictly IL‐12 dependent, inasmuch as anti‐IL‐12 antibody abrogated both responses. Most interestingly, anti‐CD40 ligand (CD40L) monoclonal antibody significantly inhibited IL‐2‐induced IL‐12 as well as IFN‐γ production. These results suggest that CD40L was expressed on T cells in the absence of TCR engagement. Indeed, purified unstimulated T cells readily expressed CD40L. IL‐2 and monocytes did not up‐regulate CD40L on resting T cells. It is proposed that low levels of CD40L expression on non‐antigen stimulated T cells are sufficient to signal through CD40 molecules on accessory cells and to induce IL‐12 secretion, which in turn can synergize with IL‐2 for the induction of IFN‐γ production,

ISSN:0014-2980    

DOI:10.1002/eji.1830260705

出版商:WILEY‐VCH Verlag GmbH    

年代:1996

数据来源: WILEY

摘要:

AbstractWe have previously shown that CD4+T cells from allergic individuals are predisposed to producing interleukin (IL)‐4 in response to allergens. IL‐4 production could be modulated by antigen concentration as well as by the type of antigen‐presenting cells (APC), with B lymphocytes inducing greater quantities of IL‐4 than monocytes. Using this system we examined IL‐4 synthesis after culture of CD4+T cells with B cells, monocytes, or both, as APC in the presence of allergen and a monoclonal antibody against CD81 (TAPA‐1), a member of the TM4 superfamily of proteins that regulates activation, proliferation and trafficking of B cells. Addition of anti‐CD81 mAb during culture enhanced IL‐4 synthesis by 2‐ to 70‐fold over that using an isotype‐matched control mAb. Furthermore, anti‐CD81 mAb enhanced IL‐4 synthesis in CD4+T cells only when CD4+T cells were cultured with B cells but not monocytes as APC, indicating that anti‐CD81 mAb affected IL‐4 synthesis in T cells via interactions with B cells. However, pretreatment of either population separately with anti‐CD81 mAb prior to culture had no effect on subsequent IL‐4 synthesis, suggesting a requirement for temporal or cooperative interactions between T and B lymphocytes. In addition, anti‐CD81 mAb enhanced IL‐4 production but reduced CD4+T cell antigen‐specific proliferation, demonstrating that IL‐4 production and proliferation by CD4+T cells were inversely related. Finally, mAb to major histocompatibility complex class II but not to anti‐CD19 also enhanced IL‐4 synthesis when B lymphocytes were used as APC. In all instances, enhancement of CD4+IL‐4 synthesis correlated with the presence of large cell aggregates in T‐B lymphocyte cocultures. These results indicate that the capacity of B cells to induce IL‐4 can be significantly enhanced by ligation of particular molecules on their surface and should aid in the design of treatments for diseases in which mod

ISSN:0014-2980    

DOI:10.1002/eji.1830260706

出版商:WILEY‐VCH Verlag GmbH    

年代:1996

数据来源: WILEY

摘要:

AbstractHomocysteine‐treated cells can be specifically lysed by cytotoxic T lymphocytes (CTL) identifiable in patients with ankylosing spondylitis and reactive arthritis. Sensitization of target cells involves disulfide bonding and the interaction between homocysteine and HLA antigens occurs in a pre‐Golgi compartment in the cells.Salmonella‐infected B cells are also lysed by homocysteine‐specific CTL, suggesting that intracellular invading microorganisms may provide homocysteine which would gain access to the newly synthesized intracellular HLA molecules and modify them inside the cells. Two different mechanisms for homocysteine modification of HLA antigens are proposed: homocysteine could bind directly to the unpaired cysteine residues in HLA antigens, or it could bind indirectly to HLA antigens through cysteine‐containing peptides bound to them. Thus, HLA antigens containing unpaired cysteine residues (e.g.HLA B27) could be modified by homocysteine directly or indirectly, while HLA antigens without unpaired cysteine residues (e.g.HLA A68) could only be modified indirectly. The results are discussed in relation to the potential involvement of homocysteine‐specific CTL in ankylosing spondylitis and reactive arthritis, both of which are related to bacterial infections, associated with HLA B27, and considered to be autoimmu

ISSN:0014-2980    

DOI:10.1002/eji.1830260707

出版商:WILEY‐VCH Verlag GmbH    

年代:1996

数据来源: WILEY

摘要:

AbstractCD40 plays critical roles in B cell proliferation and differentiation in response to T cell‐dependent antigenic stimulation. It has been suggested that CD40‐mediated biological activities are transduced by a CD40 receptor‐associated factor, CRAF1 and probably by protein tyrosine kinase Lyn and its substrates, phospholipase Cγ (PLCγ) and phosphatidylinositol‐3 kinase (PI‐3 kinase). Here, we describe the novel finding that a mitogen‐activated protein kinase (MAPK)/extracellular signal‐regulated protein kinase (ERK) cascade is involved in CD40 signaling in mouse B cells. Analysis of ERK activities in the B cell lymphoma cell line WEHI 231, which shows an increase in DNA synthesis or arrest of the cell cycle by cross‐linking of CD40 or surface IgM (sIgM) cross‐linking, respectively, indicated that one of the ERK isoforms, ERK2, was preferentially and rapidly activated after CD40 cross‐linking. The CD40‐mediated ERK2 activation was comparable to that after sIgM stimulation, although the activity was reduced toward the basal level within several minutes after stimulation. In contrast, ERK1 and ERK2 were activated to a similar extent by sIgM cross‐linking, and the activities remained stable for at least 10 min. Furthermore, similar features of differential activation of ERK isoforms were observed in normal resting B cells in CD40 and sIgM signaling. These results suggest divergent regulatory pathways for ERK1 and ERK2 activation, and they support the notion that CD40 signaling may utilize a limited set of elements in the ERK cascade. Co‐stimulation of WEHI 231 cells with anti‐CD40 mAb rescues the cells from anti‐IgM‐mediated apoptosis, whereas this co‐stimulation resulted in activation of ERK isoforms comparable to that in sIgM stimulation, without a synergistic effect. This result indicates the dominance of ERK activation in sIgM signaling over that of CD40, and it suggests that ERK activation may not be linked to the biological effect that

ISSN:0014-2980    

DOI:10.1002/eji.1830260708

出版商:WILEY‐VCH Verlag GmbH    

年代:1996

数据来源: WILEY

摘要:

AbstractThe complementary receptor pair Fas ligand: Fas controls apoptosis during activation‐induced cell death (AICD) of peripheral T cells sensitized for the Fas signal pathway by interleukin‐2 (IL‐2). In the present study, we used the bacterial superantigen staphylococcal enterotoxin B (SEB) to anergize ligand‐reactive peripheral T cells in wild‐type and Fas‐defective lpr mice. In a second step, we investigated whether apoptosis in anergized and thus operationally IL‐2‐defective peripheral T cells is triggered via the Fas signal pathway. We report here that SEB‐driven anergy induction and deletion of anergized peripheral Vβ8+T cells is similar in wild‐type and healthy C3H/lpr mice. In monitoring SEB‐driven Vβ8+T cell apoptosisin situ, we observe in both wild‐type and lpr mice an intimate association between proliferation and apoptosis of anergized Vβ8+T cells. We further show that Vβ8+T cells activatedin vitrofrom wild‐type mice express a Fas‐sensitive phenotype determined by Fas cross‐linking which causes apoptosis. In contrast, Vβ8+T cells anergizedin vivofrom wild‐type mice are Fas resistant. As expected, T cells from lpr mice activatedin vitroor anergizedin vivoare Fas resistant. Taken together, these data indicate that both in wild‐type and Fas‐defective C3H/lpr mice, anergized T cells become deleted via a Fas‐independent, prolife

ISSN:0014-2980    

DOI:10.1002/eji.1830260709

出版商:WILEY‐VCH Verlag GmbH    

年代:1996

数据来源: WILEY

摘要:

AbstractThe beneficial effect on graft survival achieved by pretransplant blood transfusions is well established. However, the type of major histocompatibility complex (MHC) mismatch between transfusion donor and recipient seems to play a role in determining the outcome. The hypothesis that this sharing of MHC antigens is correlated with the level of sensitization or tolerization was studied in mice by pretreatment with semi‐allogeneic (F1) or with fully allogeneic whole blood transfusions. Limiting dilution analysis (LDA)in vitrofor donor‐specific T helper (Thp) and cytotoxic T lymphocyte precursors (CTLp) performed on splenocytes isolated from transfused recipients 2 or 4 weeks after transfusion showed that the duration and magnitude of the response was reduced after a semi‐allogeneic compared to a fully allogeneic transfusion. After a semi‐allogeneic transfusion, both Thp and CTLp frequencies had returned to naive levels 4 weeks after transfusion, whereas after infusion of fully allogeneic blood, they remained elevated after 4 weeks. When a fully allogeneic heart was transplanted 2 or 4 weeks after transfusion, a small but significant improvement in graft prolongation (2 weeks, not significant, 4 weeks:p<0.01) was observed following pretreatment with a semi‐allogeneic transfusion (2 weeks: median survival time (MST) 30 days, 4 weeks: MST 29 days) compared to that obtained after fully allogeneic transfusion (2 weeks: MST 23 days, 4 weeks: MST 12 days). The semi‐allogeneic transfusions were correlated with a statistically significant prolonged (7 days) persistence of donor‐derived MHC class II+cells in the recipient and with reduced levels of anti‐donor MHC class I‐specific antibody formation compared to these responses after transfusion with fully allogeneic cells. These results demonstrate that pretreatment with a semi‐allogeneic blood transfusion is more tolerizing and less sensitizing than pretreatment with a fully allogeneic blood transfusion. These findings may be explained by the sharing of MHC antigens between recipient an

ISSN:0014-2980    

DOI:10.1002/eji.1830260710

出版商:WILEY‐VCH Verlag GmbH    

年代:1996

数据来源: WILEY

摘要:

AbstractThe common leukocyte antigen CD45 plays a central role in T cell activation in coupling the T cell receptor (TCR) to the phosphatidylinositol pathway via interactions with TCR‐associated protein tyrosine kinaseslckandfyn. We here demonstrate that engagement of CD45 by monoclonal antibodies (mAb) on activated T cells induces tumor necrosis factor (TNF)‐α as well as TNF‐β, interleukin (IL)‐2 and IL‐3 gene expression. When human alloreactive T cells are stimulated with mAb 4B2, which recognizes a determinant common to all CD45 isoforms, a vigorous production of TNF‐α mRNA was detected, which peaked 2 h later. Anti‐CD45 mAb cross‐linking was required. In contrast, neither mAb 10G10, which recognizes an epitope distinct from the one recognized by mAb 4B2, nor mAb UCHL‐1, a CD45RO‐specific antibody, induced any significant increase in TNF‐α transcription. Nuclear run‐on transcription assays demonstrated that CD45 cross‐linking caused transcriptional activation of the TNF‐α gene.De novoprotein synthesis was not required, since incubation with cycloheximide (CHX) did not block transcriptional activation. CHX in contrast up‐regulated TNF‐α gene expression and increased transcript half‐life, an effect that was under the control of post‐transcriptional mechanisms. Engagement of CD45 by itself did not affect transcript stability. CD45 ligation resulted in TNF‐α secretion. These results indicate that in addition to its role in TCR/CD3‐mediated T cell activation, CD45, in an epitope‐specific manner, may act as a primary signaling molecule, leading to the transcriptional regulation an

ISSN:0014-2980    

DOI:10.1002/eji.1830260711

出版商:WILEY‐VCH Verlag GmbH    

年代:1996

数据来源: WILEY