Diversity in the Molecular Architecture of Superantigen-Dependent T-Cell Signaling Complexes Eric J Sundberg, Yili Li and Roy a Mariuzza
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36 So many ways of getting in the way: diversity in the molecular architecture of superantigen-dependent T-cell signaling complexes Eric J Sundberg, Yili Li and Roy A Mariuzza Superantigens (SAGs) elicit massive T-cell proliferation CD4+ T cells [3]. Viral SAGs from the mouse mammary through simultaneous interaction with MHC and TCR tumor virus appear to stimulate CD4+-T-cell-mediated help molecules. SAGs have been implicated in toxic shock while eliciting no CD8+-T-cell response [4]. SAGs have syndrome and food poisoning, and they may also play a been implicated in the pathogenesis of a number of human pathogenic role in autoimmune diseases. The best- diseases, including toxic shock syndrome, food poisoning characterized group of SAGs are the pyrogenic bacterial [5,6] and several autoimmune disorders [7], such as Crohn’s SAGs, which utilize a high degree of genetic variation on a disease [8•] and type I diabetes [9••]. Their virulence is common structural scaffold to achieve a wide range of MHC- thought to be a result of the stimulation of extraordinarily binding and T-cell-stimulating effects while assisting pathogen large numbers of T cells and the subsequent release of evasion of the adaptive immune response. Several new massive amounts of pyrogenic and inflammatory cytokines structures of SAG–MHC and SAG–TCR complexes have such as IL-1, IL-2, TNFα and TNFβ. significantly increased understanding of the molecular bases for high-affinity peptide/MHC binding by SAGs and for TCR Recent identification and characterization of novel SAGs, Vβ domain specificity of SAGs. Using the currently available of both bacterial and viral origin, and new crystal structures SAG–MHC and SAG–TCR complex structures, models of of bacterial SAGs in complex with TCR and MHC various trimolecular MHC–SAG–TCR complexes may be molecules (with bound antigenic peptides) have greatly constructed that reveal wide diversity in the architecture of advanced our understanding of diversity in the molecular SAG-dependent T-cell signaling complexes, which architecture of MHC–SAG–TCR ternary complexes and nevertheless may result in similar signaling outcomes. the pathogenesis of SAG-mediated disease. Most of what we know about SAG structure and function derives from Addresses studies with bacterial SAGs and, thus, we will focus Center for Advanced Research in Biotechnology, WM Keck Laboratory predominantly on them in this review. for Structural Biology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850, USA A varied arsenal for immunomodulation Correspondence: Roy A Mariuzza; e-mail: [email protected] Twenty-one pyrogenic SAG family members produced by Current Opinion in Immunology 2002, 14:36–44 certain strains of the bacteria Staphylococcus aureus and 0952-7915/02/$ — see front matter Streptococcus pyogenes have so far been characterized geneti- © 2002 Elsevier Science Ltd. All rights reserved. cally. The SAGs can be divided into three genetic subfamilies (containing the SAGs SpeC, SpeJ, SpeG and Abbreviations CDR2 complementarity-determining region 2 SMEZ; SEC1, SEC2, SEC3, SEB, SSA, SpeA and SEG; and FR2 framework region 2 SEA, SEE, SED, SEH, SEI, SEJ, SEK and SEL) and two HA hemagglutinin individual branches (containing SpeH and TSST-1) that HV4 hypervariable region 4 translate loosely to functional subfamilies according to bio- β β hV 2.1 human V 2.1 chemical and structural characterization. All of these SAGs MBP myelin basic protein mVβ8.2 mouse Vβ8.2 are two-domain proteins of similar size with remarkable SAG superantigen structural conservation considering their low level of sequence identity. The carboxy-terminal domain has high Introduction structural similarity to the immunoglobulin-binding motifs Superantigens (SAGs) are immunostimulatory and disease- of streptococcal proteins G [10] and L [11], whereas the associated proteins of bacterial or viral origin that, contrary amino-terminal domain is structurally homologous to the to processed antigenic peptides, bind to MHC molecules oligosaccharide/oligonucleotide-binding (OB) fold shared by outside of the peptide-binding groove and interact with the B subunits of AB5 heat-labile enterotoxins, cholera toxin, TCR Vβ domains [1,2]. This results in the stimulation of a pertussis toxin and verotoxin [12]. The OB fold has been large fraction (up to 5%−20%) of the T-cell population, proposed to represent an ancient fold-motif that contains a compared with only 1 in 105–106 T cells during normal stable, fold-related binding face that can accommodate high antigen presentation, in which the MHC-bound peptide sequence and function variability [13]. The structural contacts the hypervariable loops of the TCR. As SAG/TCR similarities between SAGs and other bacterial proteins interactions are limited to TCR Vβ domains, SAGs are clas- suggest strongly that the former have evolved through the sically thought to stimulate T-cell subsets independently of recombination of these two smaller structural motifs [14]. T cell CD4 or CD8 surface expression. Expansion of T-cell subsets in vitro by bacterial SAGs seems to bear this out, Homologous recombination events, as opposed to random although in vivo studies suggest that they might require point-mutations, are also the primary reason for SAG Superantigen-dependent T-cell signaling complexes Sundberg, Li and Mariuzza 37 genetic polymorphism as revealed by the identification of Figure 1 24 alleles of the smez gene [15,16,17••], in which 30 out of 31 polymorphic positions have only two different amino acids. Additionally, in the case of smez, the recombination event appears to have occurred between two copies of the gene originating from different S. pyogenes strains; further, less significant, polymorphism has been attributed to individual point-mutations occurring independently in different strains [17••]. Interestingly, the extreme allelic variation of smez was found to not affect either TCR Vβ domain specificity or mitogenicity, but instead gave rise to significant antigenic differences [17••]. This can be seen most clearly in Figure 1, in which the polymorphic positions of smez have been mapped to the molecular surface of the atomic struc- ture of one of its allelic products, SMEZ-2 [18•], along with its putative MHC- and TCR-binding sites, as determined by homology modeling with the analogous SpeC complexes ([19••]; EJ Sundberg, RA Mariuzza, unpublished data). Indeed, the vast majority of allelic variation is observed outside of the TCR- and MHC-binding interfaces, Current Opinion in Immunology including a highly clustered region of polymorphism, encompassing residues 91–100, positioned well away from Allelic variation in SMEZ provides an elusive antigenic target while the functional surfaces of the smez gene product. In this maintaining superantigen function. Four views of the SMEZ-2 way, structural variation of the SMEZ molecular surface is molecular surface in which each panel shows the molecule rotated 90° likely to limit the ability of the adaptive immune response about the vertical axis, going from top left to top right, then bottom left and bottom right. Residues subject to allelic variation amongst 24 to interfere with its superantigenic function, particularly SMEZ alleles [17••] are colored green. The binding sites of TCR and via antibody-mediated neutralization. MHC class II molecules — as determined by homology modeling to the SpeC–hVβ2.1 (EJ Sundberg, RA Mariuzza, unpublished data) and Genetic variability of the common structural scaffold of the SpeC–HLA-DR2a [19••] complex structures — are outlined in yellow conserved two-domain fold of SAGs provides not only for and blue, respectively. a degree of immunological evasion but also for remarkable adaptability in MHC- and TCR-binding by distinct SAGs. To date, the family of pyrogenic SAGs have been observed the low-affinity sites of HLA-DR and -DQ diverge to use three unique interfaces to interact with MHC class sufficiently in structure to distinguish between SAGs [20]. II molecules, two of which are overlapping and found on Certain SAGs bind exclusively to the low-affinity site (e.g. the SAG amino-terminal domain and a third that is on the SEB and TSST-1), whereas others bind to both the low- carboxy-terminal domain. SAG/TCR interactions are and high-affinity sites (e.g. SEA), or to only the high-affin- mediated through the cleft formed between the amino- ity one (e.g. SpeC and SEH) of HLA-DR. Until recently, and carboxy-terminal SAG domains, allowing for specific only the low-affinity interaction had been defined by TCR contacts by residues from both of these domains. By X-ray crystallography [21,22]. The crystal structures of altering a minimal number of residues on this common SpeC bound to HLA-DR2a [19••], and of SEH in three-dimensional fold, bacterial strains are thereby able to complex with HLA-DR1 [23••], have now revealed the produce a multitude of weapons for cross-linking MHC basis for SAG binding to the high-affinity, zinc-dependent and TCR molecules. Indeed, the various strains of both site on MHC class II in atomic detail. S. aureus and S. pyogenes collectively produce collections of SAGs capable of providing them essentially the full range In both the HLA-DR2a–SpeC and HLA-DR1–SEH of SAG-dependent T-cell stimulation. complexes, the carboxy-terminal domain of the SAG con- tacts the α helix of the β1 domain of the class II molecule, Superantigen interactions with MHC class II as well as the amino-terminal portion of the bound peptide molecules and bound peptides (Figure 2a,b). There are no direct contacts with the HLA- HLA-DR molecules, with which most binding analysis DR α1 domain. The interaction is mediated, in part, by a has been performed, possess two independent binding bridging zinc ion that tetrahedrally coordinates ligands ∼ –5 β β sites for bacterial SAGs: a low-affinity site (KD 10 M) on from SpeC or SEH with His81 from the MHC 1 helix.