Differential effects of B7-1 and B7-2 on the costimulation of mouse nonspecific cytotoxic T lymphocyte development in response to anti-CD3 antibody.
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Despite extensive study, the relative contribution of B7-1 and B7-2 molecules to the costimulation of cytotoxic T lymphocyte (CTL) activation remains controversial. We used blocking mAbs to B7-1 and B7-2 molecules to determine the role of these B7 family members in the in vitro induction of mouse nonspecific CTL in response to soluble anti-CD3 mAb. Optimal induction of anti-CD3-activated killer-T (AK-T) cells was found to require interactions with B7-2 on residual accessory cells in nylon wool-nonadherent spleen cell preparations during the first 12 h of culture in the presence of anti-CD3 mAb. Because B7-1 is not expressed at high enough levels on residual accessory cells in primary T cell cultures to be an effective ligand for CD28, we used LPS-stimulated B cells, which express substantial B7-1, in addition to B7-2, to determine the contribution of B7-1 to AK-T cell development. Compared with B7-2, the contribution of B7-1 to the costimulation of AK-T cells in this system was modest because anti-B7-1 mAb had only a minimal inhibitory effect on the generation of cytotoxicity, whereas anti-B7-2 mAb strongly inhibited AK-T cell development. Anti-CD3-induced cytotoxicity of T cells from CD4 knockout mice and CD4-depleted nylon wool-nonadherent spleen cells from wild-type mice was inhibited by anti-B7-2 mAb, implying that B7-2 is able to bind directly to CD28 on CD8+ T cells and costimulate their activation. B7-1 blockade, on the other hand, did not affect the costimulation of CD8+ T cells. Blockade of B7-2/ CD28 interactions with anti-B7-2 mAb strongly inhibited granzyme B, but not perforin or Fas ligand gene expression, suggesting an explanation for the inhibitory effect of anti-B7-2 mAb on AK-T cell development. These data indicate that B7-2 is superior to B7-1 as a costimulator of mouse AK-T cell induction. (+info)
Interaction of CTLA-4 (CD152) with CD80 or CD86 inhibits human T-cell activation.
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Occupancy of CTLA-4 (cytotoxic T-lymphocyte antigen-4 or CD152) negatively regulates the activation of mouse T lymphocytes, as indicated by the fate of CTLA-4-deficient mice, by the impact of anti-CTLA-4 monoclonal antibodies (mAbs) on mouse T-cell activation in vitro and by the impact of CTLA-4 blockade on the course of experimental tumoral, autoimmune, alloimmune or infectious disease in this animal. The function of human CTLA-4, however, remains less clear. The expression and function of human CTLA-4 were further explored. CTLA-4 was expressed under mitogenic conditions only, its expression being, at least partially, dependent on the secretion of interleukin-2. Memory T cells expressed CTLA-4 with faster kinetics than naive T cells. The functional role of human CTLA-4 was assessed utilizing a panel of four anti-CTLA-4 mAbs that blocked the interaction between CTLA-4 and its ligands. These mAbs, in immobilized form, profoundly inhibited the activation of T cells by immobilized anti-CD3 mAb in the absence of anti-CD28 mAb, but co-stimulated T-cell activation in the presence of anti-CD28 mAb. Finally, and importantly, blockade of the interaction of CTLA-4 with its ligands using soluble anti-CTLA-4 mAbs, in intact form or as Fab fragments, enhanced T-cell activation in several polyclonal or alloantigen-specific CD80- or CD80/CD86-dependent assays, as measured by cytokine production, cellular proliferation or cytotoxic responses. It is concluded that interaction of CTLA-4 with its functional ligands, CD80 or CD86, can down-regulate human T-cell responses, probably by intracellular signalling events and independent of CD28 occupancy. (+info)
T suppressor lymphocytes inhibit NF-kappa B-mediated transcription of CD86 gene in APC.
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CD8+CD28- human T suppressor cells (Ts) act on APC, inhibiting their ability to elicit Th activation and proliferation. This effect is due to inhibition of the CD40 pathway which normally leads to CD80 and CD86 up-regulation. To determine whether Ts inhibit expression of B7 molecules by blocking transcription, we cloned and characterized the CD86 promoter. Mutational analysis revealed that Ts inhibit transcription driven by the CD86 promoter. The NF-kappa B binding site, at -612 of the CD86 promoter, is essential for Th-induced transcription. In cultures containing Th and Ts, Ts inhibit Th-induced NF-kappa B activation in APC. Together, these findings indicate that Ts inhibition of NF-kappa B activation in APC is a means by which they regulate the activation and proliferation of Th. (+info)
Blockade of T cell costimulation by CTLA4-Ig inhibits lung inflammation in murine hypersensitivity pneumonitis.
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Hypersensitivity pneumonitis (HP) is characterized by an influx of activated T cells in the lungs. The CD28/B7 system provides costimulatory signals essential for complete T cell activation and differentiation. We have previously demonstrated that alveolar macrophages from patients with HP have an up-regulated expression of B7 molecules. In the present study, we investigated the effect of i. p. administration of CTLA4-Ig, a CD28/B7 antagonist, on the lung inflammation of mice inoculated with Saccharoplyspora rectivirgula (SR), a major causative agent of HP. Five groups of C57BL/6 mice were intranasally instilled with SR or saline for 3 consecutive days per wk during 3 wk. CTLA4-Ig was administered starting either after 1 wk of SR challenge or 6 h before the first antigenic exposure and continued during the whole period of sensitization. A control-IgG was given similarly during the 3 wk of SR exposure. The groups included: 1, saline; 2, SR; 3, SR + control-Ig; 4, SR + CTLA4-Ig for the last 2 wk; and 5, SR + CTLA4-Ig for 3 wk. CTLA4-Ig treatment markedly decreased lung inflammation as shown by significantly fewer inflammatory cells in the bronchoalveolar lavage and in lung tissue and reduced SR-specific serum and bronchoalveolar lavage Ig levels. Production of IL-4, IL-10, and IFN-gamma by IL-2-stimulated pulmonary T cells was also decreased by CTLA4-Ig. Administration of CTLA4-Ig did not affect the SR-induced up-regulation of B7-2 expression. These results show that blockade of CD28/B7 interactions by CTLA4-Ig inhibits SR-induced lung inflammation and immune response to SR Ag in mice and may provide a novel approach in the treatment of HP. (+info)
B7 costimulation is critical for antibody class switching and CD8(+) cytotoxic T-lymphocyte generation in the host response to vesicular stomatitis virus.
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Antibody and cytotoxic T-lymphocyte (CTL) responses have critical roles in eliminating many viral infections. In addition to stimulation of the T-cell receptor, T cells require costimulatory signals to respond optimally. We evaluated the role of B7 costimulatory molecules (B7-1 and B7-2) in the immune response to viral infection using vesicular stomatitis virus (VSV) and mice lacking either B7-1 or B7-2 or both molecules. Mice lacking both B7-1 and B7-2 had essentially no anti-VSV immunoglobulin G1 (IgG1) response, decreased IgG2a responses, and normal IgM responses, while mice lacking either B7-1 or B7-2 had unaltered anti-VSV antibody responses compared to wild-type mice. Depletion of CD4(+) cells further reduced the IgG2a response in mice lacking both B7 molecules, suggesting that CD4(-) cells may supply help for IgG2a in the absence of B7 costimulation. The absence of both B7 molecules profoundly reduced generation of both primary and secondary VSV-specific class I major histocompatibility complex (MHC)-restricted CTL, whereas VSV-specific CTL responses in mice lacking either B7-1 or B7-2 were similar to those of wild-type animals. Class I MHC-restricted CTL in wild-type mice were not dependent on CD4(+) cells, suggesting that the failure of CTL in the absence of B7s is due to a lack of B7 costimulation directly to the CD8(+) CTL. These data demonstrate that B7-1 and B7-2 have critical, overlapping functions in the antibody and CTL responses to this viral infection. (+info)
Development of human T-cell leukemia virus type 1-transformed tumors in rats following suppression of T-cell immunity by CD80 and CD86 blockade.
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Host immunity influences clinical manifestations of human T-cell leukemia virus type 1 (HTLV-1) infection. In this study, we demonstrated that HTLV-1-transformed tumors could develop in immunocompetent rats by blocking a costimulatory signal for T-cell immune responses. Four-week-old WKA/HKm rats were treated with monoclonal antibodies (MAbs) to CD80 and CD86 and subcutaneously inoculated with syngeneic HTLV-1-infected TARS-1 cells. During MAb treatment for 14 days, TARS-1 inoculation resulted in the development of solid tumors at the site of inoculation, which metastasized to the lungs. In contrast, rats not treated with MAbs promptly rejected tumor cells. Splenic T cells from MAb-treated rats indicated impairment of proliferative and cytotoxic T-lymphocyte responses against TARS-1 in vitro compared to untreated rats. However, tumors grown in MAb-treated rats regressed following withdrawal of MAb therapy. Recovery of TARS-1-specific T-cell immune responses was associated with tumor regression in these rats. Our results suggest that HTLV-1-specific cell-mediated immunity plays a critical role in immunosurveillance against HTLV-1-transformed tumor development in vivo. (+info)
A negative regulatory role for Ig-alpha during B cell development.
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The development of B cells requires the expression of an antigen receptor at distinct points during maturation. The Ig-alpha/beta heterodimer signals for these receptors, and mice harboring a truncation of the Ig-alpha intracellular domain (mb-1(delta(c)/delta(c)) have severely reduced peripheral B cell numbers. Here we report that immature mb-1(delta(c)/delta(c) B cells are activated despite lacking a critical Ig-alpha-positive signaling motif. As a consequence of abnormal activation, transitional immature IgMhighIgDlow B cells are largely absent in mb-1delta(c)/delta(c) mutants, accounting for the paucity of mature B cells. Thus, Ig-alpha cytoplasmic tail truncation yields an antigen receptor complex on immature B cells that signals constitutively. These data illustrate a role for Ig-alpha in negatively regulating antigen receptor signaling during B cell development. (+info)
Simple chemicals can induce maturation and apoptosis of dendritic cells.
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As is well known in the case of Langerhans cells, dendritic cells (DCs) play a crucial role in the initiation of immunity to simple chemicals such as noted in the contact hypersensitivity. Because DCs are scattered in non-lymphoid organs as immature cells, they must be activated to initiate primary antigen-specific immune reactions. Therefore, we hypothesized that some simple chemicals must affect the function of DCs. In this paper, we first demonstrated that human monocyte-derived DCs responded to such simple chemicals as 2, 4-dinitrochlorobenzene (DNCB), 2,4,6-trinitrochlorobenzene (TNCB), 2, 4-dinitrofluorobenzene (DNFB), NiCl2, MnCl2, CoCl2, SnCl2, and CdSO4 by augmenting their expression of CD86 or human leucocyte antigen-DR (HLA-DR), down-regulating c-Fms expression or increasing their production of tumour necrosis factor-alpha (TNF-alpha). In addition, the DCs stimulated with the chemicals demonstrated increased allogeneic T-cell stimulatory function. Next, we found that, among these chemicals, only NiCl2 and CoCl2 induced apoptosis in them. Finally, we examined the effects of these chemicals on CD86 expression by three different macrophage subsets and DCs induced from the cultures of human peripheral blood monocytes in the presence of macrophage colony-stimulating factor (M-CSF), M-CSF + interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor (GM-CSF), and GM-CSF + IL-4, respectively. Among them, only DCs dramatically augmented their expression of CD86. These observations have revealed unique characteristics of DCs, which convert chemical stimuli to augmentation of their antigen presenting function, although their responses to different chemicals were not necessarily uniform in the phenotypic changes, cytokine production or in the induction of apoptosis. (+info)