Major histocompatibility complex class II-associated peptides determine the binding of the superantigen toxic shock syndrome toxin-1 (original) (raw)
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Journal of Biological Chemistry, 2006
Superantigens are bacterial or viral proteins that elicit massive T cell activation through simultaneous binding to major histocompatibility complex (MHC) class II and T cell receptors. This activation results in uncontrolled release of inflammatory cytokines, causing toxic shock. A remarkable property of superantigens, which distinguishes them from T cell receptors, is their ability to interact with multiple MHC class II alleles independently of MHC-bound peptide. Previous crystallographic studies have shown that staphylococcal and streptococcal superantigens belonging to the zinc family bind to a high affinity site on the class II β-chain. However, the basis for promiscuous MHC recognition by zinc-dependent superantigens is not obvious, because the β-chain is polymorphic and the MHC-bound peptide forms part of the binding interface. To understand how zinc-dependent superantigens recognize MHC, we determined the crystal structure, at 2.0 Å resolution, of staphylococcal enterotoxin I bound to the human class II molecule HLA-DR1 bearing a peptide from influenza hemagglutinin. Interactions between the superantigen and DR1 β-chain are mediated by a zinc ion, and 22% of the buried surface of peptide·MHC is contributed by the peptide. Comparison of the staphylococcal enterotoxin I·peptide·DR1 structure with ones determined previously revealed that zinc-dependent superantigens achieve promiscuous binding to MHC by targeting conservatively substituted residues of the polymorphic β-chain. Additionally, these superantigens circumvent peptide specificity by engaging MHC-bound peptides at their conformationally conserved N-terminal regions while minimizing sequence-specific interactions with peptide residues to enhance crossreactivity.
Protein Science, 2009
Staphylococcal enterotoxins (SEs) are superantigenic protein toxins responsible for a number of lifethreatening diseases. The X-ray structure of a staphylococcal enterotoxin A (SEA) triple-mutant (L48R, D70R, and Y92A) vaccine reveals a cascade of structural rearrangements located in three loop regions essential for binding the ␣ subunit of major histocompatibility complex class II (MHC-II) molecules. A comparison of hypothetical model complexes between SEA and the SEA triple mutant with MHC-II HLA-DR1 clearly shows disruption of key ionic and hydrophobic interactions necessary for forming the complex. Extensive dislocation of the disulfide loop in particular interferes with MHC-II␣ binding. The triple-mutant structure provides new insights into the loss of superantigenicity and toxicity of an engineered superantigen and provides a basis for further design of enterotoxin vaccines.
Proceedings of the National Academy of Sciences, 1997
Bacterial superantigens (SAgs) bind to major histocompatibility complex (MHC) class II molecules and activate T cells in a V-restricted fashion. We recently identified subsets of HLA-DR1 molecules that show selectivity for SAgs. Here, we extend these observations by showing that different cell lineages demonstrate distinct SAg-binding specificities although they all express HLA-DR1. Indeed, B cells bind staphylococcal enterotoxin A (SEA) and toxic shock syndrome toxin 1 (TSST-1) with high affinity while staphylococcal enterotoxin B (SEB) binding is barely detectable. In contrast, DR1-transfected HeLa cells show efficient binding of SEB, but not of SEA or TSST-1. We investigated the class II maturation events required for efficient interaction with SAgs and found that the ability of cells to bind and present the toxins can be drastically modulated by coexpression of the class II-associated invariant chain (Ii) and HLA-DM. SEA binding to DR1 molecules required coexpression of Ii, whereas TSST-1 binding was selectively enhanced by DM. Binding of SEB was affected by cell type-specific factors other than Ii or DM. The selectivity of SAgs for different MHC class II populations was minimally affected by HLA-DR intrinsic polymorphism and could not be explained by binding to alternative sites on DR molecules. Our results indicate that SAgs are sensitive to structural heterogeneity in class II molecules, which is consequent to the differential regulation of expression of antigen processing cofactors. Therefore, we speculate that Staphylococcus aureus have retained the ability to express numerous SAgs in adaptation to the microheterogeneity displayed by MHC class II molecules and that this may relate to their ability to infect different tissues.
The Journal of experimental medicine, 1994
Bacterial and retroviral superantigens (SAGs) stimulate a high proportion of T cells expressing specific variable regions of the T cell receptor (TCR) beta chain. Although most alleles and isotypes bind SAGs, polymorphisms of major histocompatibility complex (MHC) class II molecules affect their presentation to T cells. This observation has raised the possibility that a TCR-MHC class II interaction can occur during this recognition process. To address the importance of such interactions during SAG presentation, we have used a panel of murine T cell hybridomas that respond to the bacterial SAG Staphylococcal enterotoxin B (SEB) and to the retroviral SAG Mtv-7 when presented by antigen-presenting cells (APCs) expressing HLA-DR1. Amino acid substitutions of the putative TCR contact residues 59, 64, 66, 77, and 81 on the DR1 beta chain showed that these amino acids are critical for recognition of the SAG SEB by T cells. TCR-MHC class II interactions are thus required for T cell recognit...
Protein Science, 1996
Toxic shock syndrome toxin-1 (TSST-I) is one of a family of staphylococcal exotoxins recognized as microbial superantigens. The toxin plays a dominant role in the genesis of toxic shock in humans through a massive activation of the immune system. This potentially lethal illness occurs as a result of the interaction of TSST-1 with a significant proportion of the T-cell repertoire. TSST-I, like other superantigens, can bind directly to class I1 major histocompatibility (MHC class 11) molecules prior to its interaction with entire families of VP chains of the T-cell receptor (TCR). The three-dimensional structure of a mutant (His-135-Ala) TSST-1 was compared with the structure of the native (wild-type) TSST-1 at 2.5 A resolution. The replacement of His 135 of TSST-1 with an Ala residue results in the loss of T-cell mitogenicity and toxicity in experimental animals. This residue, postulated to be directly involved in the toxin-TCR interactions, is located on the major helix 012, which forms the backbone of the molecule and is exposed to the solvent. In the molecular structure of the mutant toxin, the helix a2 remains unaltered, but the His to Ala modification causes perturbations on the neighboring helix a1 by disrupting helixhelix interactions. Thus, the effects on TCR binding of the His 135 residue could actually be mediated, wholly or in part, by the a 1 helix.
Proceedings of the National Academy of Sciences, 1991
The interaction of the T-cell receptor (TCR) with peptide antigen plus major histocompatibility complex (MHC) protein requires both a and 13 chains of the TCR. The "superantigens" are a group of molecules that are recognized in association with MHC class II but that do not appear to conform to this pattern. Superantigens are defined as such because they cause the activation or thymic deletion of many or all T cells bearing specific TCR ig-chain variable region (Vp) elements. The strong association of particular Vps with T-cell responses to superantigens suggests that their interaction with the TCR is fundamentally different from that of most antigens. We have directly investigated the involvement of the 13 chain in recognition of a superantigen by using a secreted, truncated TCR 13 chain and the bacterial superantigen staphylococcal enterotoxin A complexed to cell-surface MHC class H. We demonstrate that this interaction is specific for the enterotoxin and is dependent on MHC class II expression by the cell. The reaction can be inhibited by antibodies against the three components of the reaction: Vp, enterotoxin, and class II. This shows that the TCR 13 chain is sufficient to mediate the interaction with a superantigen-class II complex. The TCR a chain and co-receptors such as CD4 are not required. T-cell recognition of antigen plus major histocompatibility complex (MHC) proteins requires the specificity of both a and , chains of the T-cell receptor (TCR). Small changes in the structure of the hypervariable regions of the TCR chains can have dramatic influences on reactivity to MHC and antigen (1). The "superantigens" (2) or "co-tolerogens" (3) are a class of TCR ligands that cause almost complete deletion or activation of T cells expressing certain ,3 chain variable regions (Vs) (reviewed in ref. 4). These antigens include
The Journal of Immunology
Dimerization of MHC class II molecules on the cell surface of human THP-1 monocytic cell line is a requirement for staphylococcal superantigen (SAG)-induced cytokine gene expression. The capacities of various SAG to induce this response are governed by their modes of interaction with MHC class II molecules. Staphylococcal enterotoxin A (SEA), with its two binding sites, dimerizes MHC class II molecules and subsequently induces cytokine gene expression in THP-1 cells. Here, we demonstrate that staphylococcal enterotoxin D (SED) and staphylococcal enterotoxin E (SEE) induce, similarly, IL-1β and TNF-α gene expression in these cells. Using mutated toxins that lost their binding site with the MHC class II α- or β-chain, we demonstrate that this response is also mediated by the dimerization of MHC class II molecules through two binding sites. Furthermore, SED forms Zn2+-dependent homodimers that allow multiple modes of MHC class II clustering, including ligation of α-chains (α/α), β-chai...
The Journal of Immunology, 2001
Previous studies have shown that the DM-deficient cell line, T2-I-A b , is very inefficient at presenting toxic shock syndrome toxin 1 (TSST-1) to T cells, suggesting that I-A b -associated peptides play an essential role in the presentation of this superantigen. Consistent with this, the loading of an I-A b -binding peptide, staphylococcal enterotoxin B 121-136, onto T2-I-A b cells enhanced TSST-1 presentation >1000-fold. However, despite extensive screening, no other peptides have been identified that significantly promote TSST-1 presentation. In addition, the peptide effect on TSST-1 presentation has been demonstrated only in the context of the tumor cell line T2-I-A b . Here we show that peptides that do not promote TSST-1 presentation can be converted into "promoting" peptides by the progressive truncation of C-terminal residues. These studies result in the identification of two peptides derived from IgGV heavy chain and I-E␣ proteins that are extremely strong promoters of TSST-1 presentation (47,500and 12,000-fold, respectively). We have also developed a system to examine the role of MHC class II-associated peptides in superantigen presentation using splenic APC taken directly ex vivo. The data confirmed that the length of the MHC class II-bound peptide plays a critical role in the presentation of TSST-1 by splenic APC and showed that different subpopulations of APC are equally peptide dependent in TSST-1 presentation. Finally, we demonstrated that the presentation of staphylococcal enterotoxin A, like TSST-1, is peptide dependent, whereas staphylococcal enterotoxin B presentation is peptide independent.
Crystal structure of a superantigen bound to MHC class II displays zinc and peptide dependence
The EMBO Journal, 2001
The three-dimensional structure of a bacterial superantigen, Staphylococcus aureus enterotoxin H (SEH), bound to human major histocompatibility complex (MHC) class II (HLA-DR1) has been determined by X-ray crystallography to 2.6 A Ê resolution (1HXY). The superantigen binds on top of HLA-DR1 in a completely different way from earlier co-crystallized superantigens from S.aureus. SEH interacts with high af®nity through a zinc ion with the b1 chain of HLA-DR1 and also with the peptide presented by HLA-DR1. The structure suggests that all superantigens interacting with MHC class II in a zinc-dependent manner present the superantigen in a common way. This suggests a new model for ternary complex formation with the T-cell receptor (TCR), in which a contact between the TCR and the MHC class II is unlikely.