Superantigen-driven, CD8+ T cell-mediated down-regulation: CD95 (Fas)-dependent down-regulation of human Ig responses despite CD95-independent killing of activated B cells (original) (raw)
Related papers
The Journal of Immunology
Ag recognition is an essential component for an effective T cell response. However, T cell activation is also subject to additional regulation by accessory molecules. CD28 provides essential costimulatory signals that allow T cells to proliferate, whereas molecules such as CTLA-4 and CD95 (Fas) appear to be negative regulators. Currently, which outcome predominates under conditions of antigenic challenge is poorly understood. In particular it has been suggested that one consequence of antigenic activation of T cells is the up-regulation of both CD95 and CD95 ligand, thereby exposing activated T cells to apoptotic death. We have investigated this possibility in normal human peripheral blood T cells triggered by the superantigen SEB either in the presence of endogenous APCs or transfectants expressing DR4 and CD80. In either case, we find that such activation does not expose the majority of T cells to anti-CD95-induced apoptosis as detected by annexin V externalization and DNA fragmen...
In vivo responses of CD4+ and CD8+ cells to bacterial superantigens
European Journal of Immunology, 1992
Staphylococcal enterotoxin B (SEB) is a bacterial superantigen that binds to major histocompatibility complex (MHC) class II molecules and specifically activates T cells bearing Vβ8 T cell receptor domains. We have compared several aspects of the response of CD4+ and CD8+ T cell subsets to SEB in vivo. Vβ8+ cells in both subsets proliferated to a similar extent upon SEB injection. Furthermore, mRNA for interferon-γ was induced in both subsets with similar kinetics and SEB dose-response. Finally CD8+ (but not CD4+) T cells from SEB-injected mice exhibited SEB-specific lysis of MHC class II-bearing target cells. Collectively, these data indicate that the CD4:MHC class II interaction confers no detectable selective advantage to CD4+ cells in the in vivo response to SEB. The observed effector functions of both subsets may contribute to SEB-induced immunopathology.
1998
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Staphylococcal enterotoxin B induces potent cytotoxic activity by intraepithelial lymphocytes
Immunology, 2000
In food poisoning, Staphylococcus aureus secretes staphylococcal enterotoxin B (SEB), a superantigen that causes intense T-cell proliferation and cytotoxicity. The effects of SEB on lytic activity by human intestinal intraepithelial lymphocytes (IEL) were investigated. Jejunal IEL, from morbidly obese individuals undergoing gastric bypass operations, were tested for SEB-induced cytotoxicity against C1R B-lymphoblastoid cells, HT-29 adenocarcinoma cells, or CD1dtransfected cells using the 51 Cr-release assay. Fas and Fas ligand expression were detected by immuno¯uorescence and¯ow cytometry and soluble ligand by enzyme-linked immunosorbent assay (ELISA). In the presence of SEB, IEL became potently cytotoxic against C1R cells and interferon-c (IFN-c)-precultured HT-29 cells, causing 55t10% and 31t6% lysis, respectively, greater than that by phytohaemagglutinin (PHA)-, interleukin-2 (IL-2)-, or anti-T-cell receptor (TCR)-activated IEL. SEB-stimulated peripheral blood (PB) CD8 + T cells lysed similar numbers of C1R cells but fewer HT-29 cells (53t13% and 8t5%, respectively). IEL killing of C1R cells involved interaction of major histocompatibility complex (MHC) class II with TCR, CD2 with CD58, and CD11a with CD54, and was perforin mediated. SEB-induced IEL lysis of HT-29 cells, in contrast, was caused by an unknown target cell structure, not MHC class II or CD1d, and resulted from a combination of perforin and Fas-mediated events. The potent cytotoxic activities of IEL promoted by SEB utilize two different mechanisms, depending on the surface receptors expressed by the target cells.
Rapid clearance of the bacterial superantigen staphylococcal enterotoxin B in vivo
Infection and immunity, 1996
Following bolus injection of the superantigen Staphylococcus enterotoxin B (SEB) into mice, ligand-reactive T cells are triggered to release toxic amounts of lymphokines. Subsequently, within 6 to 10 h ligand-reactive Vbeta8+ T cells become anergic and clonally expand and thereafter are deleted via apoptosis. Since the binding affinities of SEB to major histocompatibility complex (MHC) class II molecules are as low as 1.7 microM, the concentration of SEB in the fluid phase dictates the presentation via MHC class II molecules. Here, we study the pharmacokinetics of SEB in vivo and correlate pharmacokinetics with immunogenicity. We describe here how after a bolus injection of SEB, the superantigen becomes systemically distributed, with peak levels within 5 to 30 min in blood and in lymph nodes. Clearance occurs within 10 to 24 h, with the kidneys being a major route. To induce T-cell activation in vivo, SEB must be present in concentrations above 10(-4) microg/ml. These concentrations...
Immunosuppressive activity of staphylococcal enterotoxin B
Cellular Immunology, 1990
Staphylococcal enterotoxin B (SEB) binds specifically to major histocompatibility complex class II molecules on the surface of accessory cells and stimulates virtually all T cells bearing certain, but not all, T cell-receptor VP alleles. We have previously shown that this superantigen is a potent inducer of multiple regulatory T cell populations. In the present report we show that SEB induces a population of suppressor T cells which inhibits the generation of alloantigeninduced cytotoxic T cell activity. Using both negative-and positive-selection analysis, we found that this suppressor population is a CD4-CD8-CD5+ IL-2R+ T cell. This cell population inhibited both syngeneic and allogeneic cytotoxic T lymphocyte activity, but the cell population which inhibited allogeneic CTL activity was radiation sensitive. In addition, allogeneic SEB-primed cells appeared to develop cytolytic activity as a result of the additional stimulation in the mixedlymphocyte reaction culture. The relationship of the SEB-primed CD4-CD8-CD5+ T cells to related regulatory T cell populations is discussed. o 1990 Academic press, hc.
Frontiers in Immunology
Staphylococcus aureus is a common commensal and frequent opportunistic pathogen that causes invasive infections that often recur. Co-evolution with the host has led to the development of toxins that affect diverse immune cell types. Recent reports have highlighted the contributions of staphylococcal protein A (SpA). This small oligomeric secreted protein contains 4-5 homologous domains with two distinct immunoglobulin-binding sites; one for IgG Fc domains, while a separate site binds an evolutionarily conserved surface on Fab encoded by VHIII clan related genes. The Fab-binding site has been implicated in in vivo supraclonal VHIII-BCR targeted B-cell depletion by an activation induced death pathway. Yet the concept of a superantigen for B lymphocytes poses a seeming paradox. Unlike TCR that are expressed only in a membrane-associated form, BCR are expressed in both a membrane BCR form and in secreted Ig forms, which permeate virtually every part of the body at high levels. We therefore asked, why circulating immunoglobulin do not block the superantigen properties of SpA? Herein, we show that soluble IgG molecules are not in vivo inhibitors of these B-cell superantigen effects but are instead essential for potentiating these properties. We also show that the Fc subclass of circulating IgG is an indirect critical determinant of the B-cell superantigen effect. In contrast, host FcγR and complement are not required for SpA mediated in vivo B-cell depletion. Unexpectedly, after VHIII-IgG2a pretreatment SpA challenge resulted in fatal anaphylactic reactions, which we speculate may have involved FcγR interactions with mast cells and basophils. Cumulatively, our findings illuminate a cunning and potent molecular strategy by which a bacterial toxin effectively confounds the contributions of host B-lymphocytes to immune defenses.
2017
Superantigens stimulate T-lymphocyte proliferation and cytokine production, but the effects of superantigen exposure on cell function within a complex, highly regulated immune response remain to be determined. In this study, we demonstrate that superantigen exposure significantly alters the murine host response to bacterial antigens in an in vitro coculture system. Two days after exposure to the superantigen staphylococcal enterotoxin B, splenocytes cultured with Streptococcus mutans produced significantly greater amounts of gamma interferon (IFN-␥) and interleukin-12 than did sham-injected controls. The majority of IFN-␥ production appeared to be CD8 ؉ T-cell derived since depletion of this cell type dramatically reduced the levels of IFN-␥. To study host cell damage that may occur following superantigen exposure, we analyzed cytotoxicity to "bystander" fibroblast cells cultured with splenocytes in the presence of bacterial antigens. Prior host exposure to staphylococcal enterotoxin B significantly enhanced fibroblast cytotoxicity in the presence of bacteria. Neutralization of IFN-␥ decreased the amount of cytotoxicity observed. However, a greater reduction was evident when splenocyte-bacterium cocultures were separated from the bystander cell monolayer via a permeable membrane support. Increased cytotoxicity appears to be primarily dependent upon cell-cell contact. Collectively, these data indicate that overproduction of inflammatory cytokines may alter the activity of cytotoxic immune cells. Superantigen exposure exacerbates cytokine production and lytic cell activity when immune cells encounter bacteria in vitro and comparable activities could possibly occur in vivo.
Journal of Experimental Medicine, 2003
Amongst the many ploys used by microbial pathogens to interfere with host immune responses is the production of proteins with the properties of superantigens. These properties enable superantigens to interact with conserved variable region framework subdomains of the antigen receptors of lymphocytes rather than the complementarity determining region involved in the binding of conventional antigens. To understand how a B cell superantigen affects the host immune system, we infused protein A of Staphylococcus aureus (SpA) and followed the fate of peripheral B cells expressing B cell receptors (BCRs) with VH regions capable of binding SpA. Within hours, a sequence of events was initiated in SpA-binding splenic B cells, with rapid down-regulation of BCRs and coreceptors, CD19 and CD21, the induction of an activation phenotype, and limited rounds of proliferation. Apoptosis followed through a process heralded by the dissipation of mitochondrial membrane potential, the induction of the ca...