scholarly journals Superantigens promote Staphylococcus aureus bloodstream infection by eliciting pathogenic interferon-gamma (IFNγ) production that subverts macrophage function

2021 ◽  
Author(s):  
Stephen W Tuffs ◽  
Mariya I Goncheva ◽  
Stacey X Xu ◽  
Heather C Craig ◽  
Katherine J Kasper ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
T Cell ◽  
Bloodstream Infection ◽  
Mhc Class Ii ◽  
Interferon Gamma ◽  
T Cell Activation ◽  
Class Ii ◽  
Dependent Manner ◽  
Bacterial Burden ◽  
Mhc Class Ii Molecules

Staphylococcus aureus is a foremost bacterial pathogen responsible for a vast array of human diseases. Staphylococcal superantigens (SAgs) constitute a family of potent exotoxins secreted by S. aureus, and SAg genes are found ubiquitously in human isolates. SAgs bind directly to MHC class II molecules and T cell receptors, driving extensive T cell activation and cytokine release. Although these toxins have been implicated in serious disease including toxic shock syndrome, we aimed to further elucidate the mechanisms by which SAgs contribute to staphylococcal pathogenesis during septic bloodstream infections. As most conventional mouse strains respond poorly to staphylococcal SAgs, we utilized transgenic mice encoding humanized MHC class II molecules (HLA-DR4) as these animals are much more susceptible to SAg activity. Herein, we demonstrate that SAgs contribute to the severity of S. aureus bacteremia by increasing bacterial burden, most notably in the liver. We established that S. aureus bloodstream infection severity is mediated by CD4+ T cells and interferon-gamma (IFNγ) is produced to very high levels during infection in a SAg-dependent manner. Bacterial burden and disease severity were reduced by antibody blocking of IFNγ, phenocopying isogenic SAg deletion mutant strains. Additionally, cytokine analysis demonstrated that the immune system was skewed towards a proinflammatory response that was reduced by IFNγ blocking. Infection kinetics and flow cytometry analyses suggested this was a macrophage driven mechanism, which was confirmed through macrophage depletion experiments. Further validation with human leukocytes indicated that excessive IFNγ allowed S. aureus to replicate at a higher rate within macrophages. Together, this suggests that SAgs promote S. aureus survival by manipulating immune responses that would otherwise be effective at clearing S. aureus. This work implicates SAg toxins as critical targets for preventing persistent or severe S. aureus disease.

scholarly journals Major histocompatibility complex independent clonal T cell anergy by direct interaction of Staphylococcus aureus enterotoxin B with the T cell antigen receptor.

1992 ◽  
Vol 175 (6) ◽  
pp. 1493-1499 ◽  
Author(s):  
C R Hewitt ◽  
J R Lamb ◽  
J Hayball ◽  
M Hill ◽  
M J Owen ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class Ii ◽  
Direct Interaction ◽  
Class Ii ◽  
Cell Antigen ◽  
Histocompatibility Complex ◽  
Mhc Class Ii Molecules

The Staphylococcal enterotoxin superantigens stimulate vigorous responses in T cells bearing certain T cell antigen receptor (TCR) V beta regions. In addition to activation, these superantigens also impart negative signals to T cells resulting in a profound state of unresponsiveness or anergy. The Staphylococcus aureus enterotoxins (SE) B and C2 bind to a closely related site on major histocompatibility complex (MHC) human leukocyte antigen (HLA)-DR1 molecules. Only SEB, however, interacts with the TCR V beta 3 region of HA1.7, a human HLA-DR1 restricted T cell clone specific for influenza haemagglutinin. In competition experiments, we demonstrated that the induction of anergy in HA1.7 by SEB is unaffected by the presence of SEC2. These results suggest that SEB-induced anergy is MHC independent and involves a direct interaction between the TCR and SEB. To resolve definitively whether SEB binds directly to T cells in the absence of MHC class II molecules, the cDNAs encoding the HA1.7 TCR were transfected into an MHC class II-negative human T cell line. The addition of SEB to these transfectants resulted in the downregulation of cell surface TCR expression, an increase in the concentration of intracellular calcium ions, the production of lymphokines, and reduced responsiveness to a subsequent challenge with SEB. We conclude that SEB interacts directly with the TCR in the absence of cointeraction with MHC class II molecules, and that this interaction may induce anergy in HA1.7.

scholarly journals The CD4 molecule is not always required for the T cell response to bacterial enterotoxins.

1991 ◽  
Vol 173 (2) ◽  
pp. 367-371 ◽  
Author(s):  
R P Sékaly ◽  
G Croteau ◽  
M Bowman ◽  
P Scholl ◽  
S Burakoff ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Response ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Class Ii ◽  
T Cell Response ◽  
Cd4 Cells ◽  
Mhc Class Ii Molecules

T cells respond in a V beta-restricted fashion to bacterial enterotoxins bound to major histocompatibility complex (MHC) class II molecules. The requirement for CD4 in MHC class II-restricted T cell responses is very well established. We have assessed the role of CD4 in the T cell response to the bacterial enterotoxins Staphylococcal enterotoxin A (SEA), SEB, and toxic shock syndrome toxin 1. Three CD4- murine T cell hybridomas were transfected with the human CD4 molecule and assayed for interleukin 2 production in the presence of accessory cells bearing human MHC class II molecules and of the appropriate enterotoxin. The results clearly indicate that CD4- cells responded even to suboptimal concentrations of enterotoxin(s) equally well as CD4+ cells. Furthermore, expression of CD4 did not result in the acquisition of previously undetectable reactivity to enterotoxins. These results suggest that unlike the case with antigen-specific responses, formation of a T cell receptor-CD3/CD4 supramolecular complex is not always essential for T cell activation by bacterial enterotoxins.

scholarly journals CD4 T-Cell Suppression by Cells from Toxoplasma gondii-Infected Retinas Is Mediated by Surface Protein PD-L1

2010 ◽  
Vol 78 (8) ◽  
pp. 3484-3492 ◽  
Author(s):  
Elizabeth Charles ◽  
Sunil Joshi ◽  
John D. Ash ◽  
Barbara A. Fox ◽  
A. Darise Farris ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Flow Cytometric Analysis ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Dependent Manner ◽  
Retinal Cells

ABSTRACT In the inflamed retina, CD4+ T cells can cause retinal damage when they are not properly regulated. Since tissue expression of major histocompatibility complex (MHC) class II and costimulatory molecules is a key mechanism for regulating effector T cells, we tested the hypothesis that upregulation of these proteins in the retina contributes to the regulation of CD4 T cells. Here we report that in retinas infected with the protozoan parasite Toxoplasma gondii, MHC class II is upregulated on infiltrating leukocytes as well as on resident retinal cells, including photoreceptors. Flow cytometric analysis indicated that B7 costimulatory family members (CD80, CD86, ICOS-L, and programmed death ligand 2 [PD-L2]) were not expressed on class II+ cells. In contrast, PD-L1 (also named B7-H1 or CD274) was expressed on the majority of both hematopoietic and resident retinal MHC class II-expressing cells. Retinal cells from Toxoplasma-infected animals were able to suppress T-cell activation in a PD-L1-dependent manner. Finally, we demonstrate that the expression of MHC class II and PD-L1 was critically dependent on gamma interferon (IFN-γ) expression. These data suggest that retinal MHC class II and PD-L1 expression is a novel mechanism by which the retina protects itself from CD4 T-cell-mediated immune damage in ocular toxoplasmosis and other types of retinal immune responses.

scholarly journals Suppression of Staphylococcus aureus Superantigen-Independent Interferon Gamma Response by a Probiotic Polysaccharide

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Wonbeom Paik ◽  
Francis Alonzo ◽  
Katherine L. Knight
Keyword(s):  
Staphylococcus Aureus ◽  
Bloodstream Infection ◽  
Interferon Gamma ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Interleukin 12 ◽  
Dependent Manner ◽  
Content Type ◽  
Ifn Γ

ABSTRACT Staphylococcus aureus is a Gram-positive opportunistic pathogen that causes a variety of diseases. Bloodstream infection is the most severe, with mortality rates reaching 20 to 50%. Exopolysaccharide (EPS) from the probiotic Bacillus subtilis reduces bacterial burden and inflammation during S. aureus bloodstream infection in mice. Protection is due, in part, to hybrid macrophages that restrict S. aureus growth through reactive oxygen species and to limiting superantigen-induced T cell activation and interferon gamma (IFN-γ) production during infection. A decrease in IFN-γ production was observed within 24 h after infection, and here, we investigated how EPS abrogates its production. We discovered that S. aureus uses a rapid, superantigen-independent mechanism to induce host IFN-γ and that this is mediated by interleukin-12 (IL-12) activation of NK cells. Furthermore, we found that EPS limits IFN-γ production by modulating host immunity in a Toll-like receptor 4 (TLR4)-dependent manner, a signaling pathway that is required for EPS-mediated protection from S. aureus infection in vivo. We conclude that EPS protects hosts from acute bloodstream S. aureus infection not only by inducing macrophages that restrict S. aureus growth and inhibit superantigen-activated T cells but also by limiting NK cell production of IFN-γ after S. aureus infection in a TLR4-dependent manner.

scholarly journals Activation of Human T Cells by Major Histocompatability Complex Class II Expressing Neutrophils: Proliferation in the Presence of Superantigen, But Not Tetanus Toxoid

Blood ◽  
1997 ◽  
Vol 89 (11) ◽  
pp. 4128-4135 ◽  
Author(s):  
Neil A. Fanger ◽  
Chunlei Liu ◽  
Paul M. Guyre ◽  
Kathleen Wardwell ◽  
Jerome O'Neil ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Tetanus Toxoid ◽  
Cell Activation ◽  
Class Ii ◽  
Polymorphonuclear Neutrophils ◽  
Gm Csf ◽  
Ifn Γ ◽  
Mhc Class Ii Molecules

Abstract The primary function of polymorphonuclear neutrophils (PMN) in the immune response appears to be acute phagocytic clearance of foreign pathogens and release of inflammatory mediators. Consistent with their assumed lack of major histocompatibility complex (MHC) class II expression, PMN have not been considered to play a role in antigen presentation and T-cell activation. However, recent reports have shown that human PMN can express MHC class II molecules both in vitro and in vivo after stimulation with either granulocyte-macrophage colony-stimulating factor (GM-CSF ) or interferon-γ (IFN-γ). Thus, under appropriate conditions, PMN could play a significant role in immune regulation, including T-cell activation. In this report, we demonstrate that human class II–expressing PMN can serve as accessory cells in superantigen (SAg)-mediated T-cell activation. This accessory activity for SAg presentation was present only after induction of MHC class II expression, and was especially pronounced following culture of PMN with GM-CSF plus IFN-γ, which acted synergistically to induce MHC class II molecules on PMN. Moreover, the level of MHC class II expression and the magnitude of SAg-induced T-cell responses were found to be highly correlated and distinctly donor dependent, with PMN from some donors repeatedly showing fivefold higher responses than PMN from other donors. On the other hand, culture of PMN with GM-CSF plus IFN-γ under conditions that resulted in optimal MHC class II expression did not enable them to function as antigen-presenting cells for either intact tetanus toxoid (TT) or for a TT peptide. These results delineate a new pathway for T-cell activation by SAg that may play an important role in the severity of SAg-induced inflammatory responses. They also identify a donor-specific polymorphism for induction of PMN MHC class II expression which may be of significance for therapies involving GM-CSF and IFN-γ.

scholarly journals Identification of a CD4+ T cell-stimulating antigen of pathogenic bacteria by expression cloning.

1995 ◽  
Vol 182 (6) ◽  
pp. 1751-1757 ◽  
Author(s):  
S Sanderson ◽  
D J Campbell ◽  
N Shastri
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Pathogenic Bacteria ◽  
Genomic Library ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Expression Cloning

Identifying the immunogenic proteins that elicit pathogen-specific T cell responses is key to rational vaccine design. While several approaches have succeeded in identifying major histocompatibility complex (MHC) class I bound peptides that stimulate CD8+ T cells, these approaches have been difficult to extend to peptides presented by MHC class II molecules that stimulate CD4+ T cells. We describe here a novel strategy for identifying CD4+ T cell-stimulating antigen genes. Using Listeria monocytogenes-specific, lacZ-inducible T cells as single-cell probes, we screened a Listeria monocytogenes genomic library as recombinant Escherichia coli that were fed to macrophages. The antigen gene was isolated from the E. coli clone that, when ingested by the macrophages, allowed generation of the appropriate peptide/MHC class II complex and T cell activation. We show that the antigenic peptide is derived from a previously unknown listeria gene product with characteristics of a membrane-bound protein.

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