The structure of superantigen complexed with TCR and MHC reveals novel insights into superantigenic T cell activation

Abstract

superantigens (sAgs) are bacterial toxins that interact with immunoreceptors, T cell receptor (TCR) and major histocompatibility complex (mHC) class II, conventionally through the variable β-domain of TCR (TCRVβ). They induce a massive release of cytokines, which can lead to diseases such as food poisoning and toxic shock syndrome. In this study, we report the X-ray structure of the ternary complex between staphylococcal enterotoxin H (sEH) and its human receptors, mHC class II and TCR. The structure demonstrates that sEH predominantly interacts with the variable α-domain of TCR (TCRVα), which is supported by nuclear magnetic resonance (nmR) analyses. Furthermore, there is no contact between mHC and TCR upon complex formation. structural analyses suggest that the major contact points to TCRVα are conserved among other bacterial sAgs. Consequently, a new dimension of sAg biology emerges, suggesting that in addition to the conventional interactions with the TCRVβ domain, sAgs can also activate T cells through the TCRVα domain.

Structure of the Superantigen Staphylococcal Enterotoxin B in Complex with TCR and Peptide–MHC Demonstrates Absence of TCR–Peptide Contacts

“…So far, only two complete TCR-SAg-MHC complexes are available. One describes how staphylococcal enterotoxin H (SEH) binds to MHC and TCR (11). SEH is an atypical SAg because it activates and binds T cells through the TRAV domain (5,12).…”

“…Moreover, SEH binds on top of the peptide-MHC complex and contacts the peptide backbone (13). Hence it is clear that SEH prevents interactions between TCR and the peptide by steric hindrance (11). The other available TCR-SAg-MHC structure is of the Mycoplasma arthritidis mitogen, which is structurally unrelated to the staphylococcal enterotoxins and streptococcal pyrogenic exotoxins, but still binds TCR and MHC class II (14).…”

“…and 25 mg/l kanamycin. The periplasmic content was released and purified according to a previous protocol (11), except cationic exchange in 20 mM HEPES pH 7.0 with a 0-200 mM NaCl gradient.…”

“…MHC class II, HLA-DR1 (a-chain DR*0101 and b-chain DRB1*0101) was produced as described previously (11,18), with minor exceptions. Changes are as follows: E. coli BL21 (DE3) Star cells (Invitrogen) were used, cells were centrifuged and resuspended in fresh 2xYT media before IPTG induction, and refolding was carried out by dilution to a final concentration of 0.24 mM of each chain in 2 l refolding buffer.…”

MMTV Superantigens Coerce an Unconventional Topology between the TCR and MHC Class II

“…Most of the SAG-mediated T cell signaling complexes outline a typical interaction between the TCR Vb and the SAG, where the Va sometimes participates in MHCII b-chain binding (4,76,77). Consequently, Vb/MHCII a-chain contacts are sterically precluded by the bound bacterial SAGs.…”