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* Department of Infectious Diseases, Faculty of Medicine, Imperial College School of Science, Technology, and Medicine, London, United Kingdom; and
Department of Molecular Medicine, School of Medicine, University of Auckland, Auckland, New Zealand
The gene encoding streptococcal mitogenic exotoxin Z (SMEZ) was
disrupted in Streptococcus pyogenes. Despite the
presence of other superantigen genes, mitogenic responses in human and
murine HLA-DQ transgenic cells were abrogated when cells were
stimulated with supernatant from the
smez- mutant compared with the parent
strain. Remarkably, disruption of smez led to a complete
inability to elicit cytokine production (TNF-
, lymphotoxin-,
IFN-
, IL-1 and -8) from human cells, when cocultured with
streptococcal supernatants. The potent effects of SMEZ were apparent
even though transcription and expression of SMEZ were barely
detectable. Human V
8+ T cell proliferation in response
to S. pyogenes was SMEZ-dependent. Cells from HLA-DQ8
transgenic mice were 3 logs more sensitive to SMEZ-13 than cells from
HLA-DR1 transgenic or wild-type mice. In the mouse, SMEZ targeted the
human V8+ TCR homologue, murine V11, at the expense
of other TCR T cell subsets. Expression of SMEZ did not affect
bacterial clearance or survival from peritoneal streptococcal infection
in HLA-DQ8 mice, though effects of SMEZ on pharyngeal infection are
unknown. Infection did lead to a rise in V11+ T cells in
the spleen which was partly reversed by disruption of the
smez gene. Most strikingly, a clear rise in murine
V4+ cells was seen in mice infected with the
smez- mutant S.
pyogenes strain, indicating a potential role for SMEZ as a
repressor of cognate anti-streptococcal
responses.
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