Understanding the mechanism of action of bacterial superantigens from a decade of research

Staphylococcal enterotoxin H (SEH) is a bacterial superantigen secreted by Staphylococcus aureus. Superantigens are presented on the MHC class II and activate large amounts of T cells by cross-linking APC and T cells. In this study, RT-PCR was used to show that SEH stimulates human T cells via the Vα domain of TCR, in particular Vα10 (TRAV27), while no TCR Vβ-specific expansion was seen. This is in sharp contrast to all other studied bacterial superantigens, which are highly specific for TCR Vβ. It was further confirmed by flow cytometry that SEH stimulation does not alter the levels of certain TCR Vβ. In a functional assay addressing cross-reactivity, Vβ binding superantigens were found to form one group, whereas SEH has different properties that fit well with Vα reactivity. As SEH binds on top of MHC class II, an interaction between MHC and TCR upon SEH binding is not likely. This concludes that the specific expansion of TCR Vα is not due to contacts between MHC and TCR, instead we suggest that SEH directly interacts with the TCR Vα domain.

Section: Seh Does Not Induce a Tcr V␤-specific Expansion Upon T Cell supporting

confidence: 80%

Staphylococcal Enterotoxin H Induces Vα-Specific Expansion of T Cells

Petersson

Pettersson

Skartved

et al. 2003

“…As shown in Fig. 7B, presentation of all epitopes by SaI/CIITA and SaI/A k /DM, except HEL [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] , is inhibited by chloroquine, suggesting endosomal trafficking is required for most epitopes. BFA prevents transport of newly synthesized proteins from the ER, and hence blocks trafficking of newly synthesized MHC class II molecules, while having minimal effect on recycling class II (33,36).…”

Section: H2-o Affects Presentation Of Exogenous Ags By Newly Synthesimentioning

confidence: 99%

H2-O Inhibits Presentation of Bacterial Superantigens, but Not Endogenous Self Antigens

Ostrand‐Rosenberg

2001

H2-O/HLA-DO are MHC class II accessory molecules that modulate exogenous Ag presentation. Most class II accessory molecules are expressed in all professional APC; however, H2-O is only expressed in B cells and medullary thymic epithelial cells. Because B cells present exogenous Ags and superantigens (SAgs), and medullary thymic epithelial cells are specialized APC for self Ags during negative selection in the thymus, we have hypothesized that H2-O might play a role in MHC class II-restricted SAg and self Ag presentation. In this study, we demonstrate that H2-O expression inhibits presentation of the bacterial SAgs staphylococcal enterotoxins A and B to four SAg-reactive T hybridoma cells. In contrast, H2-O has no effect on presentation of endogenous self Ags, as measured by tumorigenicity in vivo and Ag presentation to three self Ag-specific T hybridoma cells. Additional experiments suggest that H2-O inhibits presentation of exogenous Ags by both newly synthesized and recycling MHC class II molecules. These data suggest H2-O may have a physiological role in tolerance induction and SAg-mediated toxic shock.

“…Staphylococcal exotoxins, including toxic shock syndrome toxin-1 and staphylococcal enterotoxin serotypes A, B, C1, C2, C3, D, E, G, H, and I, cause toxic shock syndrome in both humans and animals (16). These microbial products are all members of a family of structurally related proteins called SAgs that bind to the MHC class II molecules on the APCs and to TCR bearing-specific V␤ fragments (17). This trimolecular interaction leads to massive proliferation of T cells and uncontrolled release of proinflammatory cytokines, including IL-1, IL-2, IFN-␥, and TNF-␣, which causes life-threatening toxic shock syndrome (16).…”

Section: A Ccumulating Evidence Indicates That Cd4mentioning

confidence: 99%

CD4+CD25+ and CD4+CD25− T Cells Act Respectively as Inducer and Effector T Suppressor Cells in Superantigen-Induced Tolerance

Feunou

Poulin

Habran

et al. 2003

The repeated injection of low doses of bacterial superantigens (SAg) is known to induce specific T cell unresponsiveness. We show in this study that the spleen of BALB/c mice receiving chronically, staphylococcal enterotoxin B (SEB) contains SEB-specific CD4+ TCRBV8+ T cells exerting an immune regulatory function on SEB-specific primary T cell responses. Suppression affects IL-2 and IFN-γ secretion as well as proliferation of T cells. However, the suppressor cells differ from the natural CD4+ T regulatory cells, described recently in human and mouse, because they do not express cell surface CD25. They are CD152 (CTLA-4)-negative and their regulatory activity is not associated with expression of the NF Foxp3. By contrast, after repeated SEB injection, CD4+CD25+ splenocytes were heterogenous and contained both effector as well as regulatory cells. In vivo, CD4+CD25− T regulatory cells prevented SEB-induced death independently of CD4+CD25+ T cells. Nevertheless, SEB-induced tolerance could not be achieved in thymectomized CD25+ cell-depleted mice because repeated injection of SEB did not avert lethal toxic shock in these animals. Collectively, these data demonstrate that, whereas CD4+CD25+ T regulatory cells are required for the induction of SAg-induced tolerance, CD4+CD25− T cells exert their regulatory activity at the maintenance stage of SAg-specific unresponsiveness.