In vivo staphylococcal superantigen-driven polyclonal Ig responses in mice: dependence upon CD4+ cells and human MHC class II (original) (raw)
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Infection and autoimmunity: Lessons of animal models
European Journal of Microbiology and Immunology, 2011
While the key initiating processes that trigger human autoimmune diseases remain enigmatic, increasing evidences support the concept that microbial stimuli are among major environmental factors eliciting autoimmune diseases in genetically susceptible individuals. Here, we present an overview of evidences obtained through various experimental models of autoimmunity for the role of microbial stimuli in disease development. Disease onset and severity have been compared in numerous models under conventional, specific-pathogen-free and germ-free conditions. The results of these experiments suggest that there is no uniform scheme that could describe the role played by infectious agents in the experimental models of autoimmunity. While some models are dependent, others prove to be completely independent of microbial stimuli. In line with the threshold hypothesis of autoimmune diseases, highly relevant genetic factors or microbial stimuli induce autoimmunity on their own, without requiring further factors. Importantly, recent evidences show that colonization of germ-free animals with certain members of the commensal flora [such as segmented filamentous bacteria (SFB)] may lead to autoimmunity. These data drive attention to the importance of the complex composition of gut flora in maintaining immune homeostasis. The intriguing observation obtained in autoimmune animal models that parasites often confer protection against autoimmune disease development may suggest new therapeutic perspectives of infectious agents in autoimmunity.
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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European Journal of Immunology, 1993
Injection of bacterial superantigens such as staphylococcal enterotoxin B (SEB) in adult mice results in initial proliferation of SEB-responsive Vβ8+ T cells followed by induction of a state of non-responsiveness frequently referred to as clonal anergy. We show here that SEB-induced anergy involves selective changes in lymphokine production and that it affects CD4+ Vβ 8+ and CD8+ Vβ 8+ T cells in different fashions. Whereas both CD4+ Vβ 8+ and CD8+ Vβ 8+ cells from anergic mice exhibit strongly reduced proliferative capacity and interleukin(IL)-2 production upon restimulation with SEB either in vivo or in vitro the CD8+ subset from SEB-injected mice produces other lymphokines (such as interferon(IFN)-γ) at normal or slightly increased levels in response to SEB. Changes in the levels of production of IL-2 and IFN-γ protein correlated well with mRNA accumulation both in vivo and in vitro. Collectively these data suggest that superantigen-induced anergy involves selective changes in signal transduction and/or gene regulation in T lymphocytes.
Journal of Immunological Methods, 1998
We have developed a novel co-culture system in which murine splenocytes are cultured with live bacteria in the presence Ž . of a bacteriostatic antibiotic. Superantigens, like staphylococcal enterotoxin B SEB are important factors in bacterial pathogenicity. Research has shown that superantigens affect numerous immune cell types, either directly or indirectly, yet their involvement in pathogenic mechanisms remains poorly defined. In these studies, we utilize the co-culture system to Ž . study how superantigen pretreatment affects interferon-g IFN-g production by splenocytes co-cultured with gram-positive bacteria. Streptococcus mutans, S. sanguis and Bacillus subtilis were tested for susceptibility to a panel of antibiotics. Spectinomycin was found to maintain a bacteriostatic state of approximately 10 5 bacteria ml y1 at optimal concentrations for each bacterial strain. Co-culturing splenocytes with bacteria did not affect splenocyte viability and cultured splenocytes responded to mitogenic stimulation as expected. Two days after SEB pretreatment, isolated splenocytes cultured with either Streptococcus species produced 10-15 times more IFN-g than splenocytes from sham-injected controls; however, no differences in CD4 q or CD8 q T cell populations appeared in cultures with or without bacteria. Splenocytes isolated four days after SEB treatment did not produce significant amounts of IFN-g in co-culture. Co-cultures containing live bacteria Ž . produced four times more IFN-g than cultures containing heat-killed bacteria. Splenocytes depleted of natural killer NK cells prior to SEB treatment produced 25% less IFN-g after 20 h co-culturing with S. mutans. T lymphocytes were identified to be the major producer of IFN-g at this time point by intracellular cytokine staining. Apparently SEB exposure primes a response to live bacteria and the response is evident two days after initial exposure. The in vitro co-culture system allows us to observe host responses to bacteria in the context of the multicellular interdependent immune response. With this assay we can more closely 'mimic' in vivo events, particularly immune cell interactions in microfloral environments, to study how the pathogenic effects of superantigens alter this response. q 1998 Elsevier Science B.V.
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.
Auto-presentation of Staphylococcal enterotoxin A by mouse CD4<sup>+</sup> T cells
Open Journal of Immunology, 2011
The currently accepted model for superantigen (SAg) induced T cell activation suggests that SAg, without being processed, cross link both MHC class II, from Antigen Presenting Cells (APC), and V-, from T-cell receptor (TCR), initiating nonspecific T-cell activation. This T-cell proliferation induces a massive cytokine release associated with several human diseases. It is thought that murine CD4 + T cells do not express MHC class-II molecules. However, we discovered that a subtype of mouse naïve CD4 + T cells expresses MHC class II on their cell surface and that these CD4 + T cells can perform the role of both APC and T cells, able to present Staphylococcal enterotoxin A (SEA) to itself or neighboring CD4 + T cells via MHC class II, thus inducing massive CD4 + T cell proliferation. Treatment with neutralizing anti MHC class II antibody inhibits this CD4 + T cell proliferation response. The fact that murine CD4 + T cells express MHC class II offers new insight about SAg activity. Based on our findings, we propose revising and extending previous models for SAg induced T cell activation, altering previous models of MHC class II restriction of T cell responses to SEA as well as the requirement for SAg processing.