International Immunology Advance Access published online on August 7, 2006
International Immunology, doi:10.1093/intimm/dxl076
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1 Department of Infectious Diseases, Faculty of Medicine, Imperial College London W12 0NN, UK; Division of Medicine, Brighton and Sussex Medical School, Medical Research Building, University of Sussex, Falmer BN1 9PS, UK
* To whom correspondence should be addressed. Superantigens (Sags) induce large-scale stimulation of T lymphocytes by a mechanism distinct from conventional antigen presentation, involving direct MHC binding and stimulation of TCR families based on V
Received August 17, 2005
Accepted July 11, 2006
Article
The TCR V
Martin Llewelyn 1 *, Shiranee Sriskandan 2, Nadia Terrazzini 3, Jonathan Cohen 3, and Daniel M. Altmann 2
signature of bacterial superantigens spreads with stimulus strength
2 Department of Infectious Diseases, Faculty of Medicine, Imperial College London W12 0NN, UK
3 Division of Medicine, Brighton and Sussex Medical School, Medical Research Building, University of Sussex, Falmer BN1 9PS, UK
Martin Llewelyn, E-mail: m.j.llewelyn{at}bsms.ac.uk
Abstract 
gene usage. The specific V targets of a given Sag have, since the earliest studies in murine models, been considered a hallmark of that toxin. Bacterial Sags are implicated in the aetiology of a wide range of human diseases, although their role has been most clearly defined in toxic shock syndrome. While Sags have been defined by the V-specific changes in T cell repertoire they induce, human studies of in vitro stimulation or analysis of cells from infected patients have produced inconsistent findings. Here we have evaluated the contribution of HLA allelic polymorphisms and strength of stimulus to this response. We show that there are differences in binding and presentation of the staphylococcal Sag, staphylococcal enterotoxin A (SEA), by different HLA-DR alleles. We also show that the TCR V response, previously thought to be a fixed property defining a given Sag, varies with stimulus strength such that a broader repertoire of response is seen at higher concentrations or following presentation by high-binding class II types. Responses of human V8 and V1 to SEA, V5 to SEB and of V12 and V13 to streptococcal pyrogenic exotoxin A are absolutely dependent on stimulus strength. These findings have important implications for heterogeneity in the response to Sags and the consequent differences in susceptibility to severe toxic shock.
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