Subtype‐specific interactions of type C staphylococcal enterotoxins with the T‐cell receptor

Abstract

The goal of this study was to investigate the molecular interaction between superantigens and the T-cell receptor (TCR). Using a quantitative polymerase chain reaction (PCR) to assess T-cell proliferation profiles, we found that SEB, SEC1, SEC2 and SEC3 expanded human T cells bearing V beta 3, V beta 12, V beta 13.2, V beta 14, V beta 15, V beta 17 and V beta 20. SEC2 and SEC3 have the additional ability to expand T cells bearing V beta 13.1, and their expansion of V beta 3 was markedly reduced compared to SEB and SEC1. Based on the activity of SEC1 mutants containing single amino acid substitutions, we concluded that the differential abilities of these native toxins to stimulate V beta 3 and V beta 13.1 was determined by the residue in position 26, located in the base of the SEC alpha 3 cavity. The SEC1 mutant, in which Val in position 26 was substituted with the analogous SEC2/SEC3 residue (Tyr), generated a V beta expansion profile that was indistinguishable from those generated by SEC2 and SEC3. Using these findings, the co-ordinates of a recently reported murine TCR beta-chain crystal structure, and other documented information, we propose a compatible molecular model for the interaction of SEC3 with the T-cell receptor. In this model complex, the complementarity-determining regions (CDRs) 1 and 2 and the hypervariable loop 4 of the V beta element contact SEC3 predominantly through residues in the alpha 3 cavity of the toxin. CDR3 of the beta chain is not involved in any toxin contacts. The proposed model not only includes contacts identified in previous mutagenesis studies, but is also consistent with the ability of tyrosine and valine in position 26 to differentially affect the expansion of V beta s 3 and 13.1 by the SEC superantigens.

Biochemical and Biological Properties of Staphylococcal Enterotoxin K

“…Only one other characterized toxin stimulates TCR V␤ 5.1 (SEE), and no other toxins have been observed to stimulate V␤ 5.2 or 6.7. The structure of the PTSAg must dictate the TCR V␤ profile of the stimulated T cells (10,16,18). It has been seen with other toxins that a large region at the top front (in the standard view of SEB and -C) or top back of TSST-1 is important for TCR binding (11,13,22,28).…”

Human CD4+ Memory T Cells Are Preferential Targets for Bystander Activation and Apoptosis

“…An in vitro system was designed whereby human PBMC were stimulated with SEB, a superantigen with a well-characterized specificity (29), and responses were monitored among the directly activated population of V␤17 ϩ T cells and the nonspecific or bystander population of V␤13.1 ϩ T cells. There are numerous advantages to this system: a large proportion of the T cell repertoire is directly stimulated by SEB; the V␤13.1 subset is well characterized as nonresponsive to SEB (29 -32); this nonresponsive bystander subset represents a sizeable proportion of T cells in most donors, facilitating the identification of rare events; finally, and perhaps most importantly, the V region of the TCR ␤-chain is the sole determinant of superantigen specificity, and as such, the relative promiscuity of the TCR peptide recognition site is irrelevant.…”

Analysis of the interaction between the bacterial superantigen streptococcal pyrogenic exotoxin A (SpeA) and the human T‐cell receptor

“…The bacterial superantigens SEA, SEB, and SEC2 are believed to interact with one of the CDRs of the TCR (Bellio et al, 1994;Deringer, 1996;Patten et al, 1993;Pontzer et al, 1992). To determine if CDRs play a role in the SpeA-TCR interaction, we attempted to inhibit SpeA stimulation of PBMC with CDR-specific peptides.…”

“…Two recent publications illustrate that both SEC2 and SEC3 bind the three CDR regions (Deringer et al, 1996;Fields et al 1996). Fields et al (1996) crystallized SEC3 complexed with a purified mouse V␤ chain.…”

“…The various superantigens appear to bind to the complementary determining regions (CDR) of the TCR V␤ chain (Bellio et al, 1994;Deringer et al, 1996;Mollick et al, 1993;Patten et al, 1993;Pontzer et al, 1992). CDR1 through CDR4 are the hypervariable, solventexposed loops formed between the ␤-sheets of the V␤ chain (Chothia et al, 1988;Davis and Bjorkman, 1988).…”