Virtually all
cystic fibrosis (CF) patients become infected with Pseudomonas aeruginosa, and once the
infection is established, the organism is rarely cleared. One of the P. aeruginosa
virulence factors,
exoenzyme S, has been shown to correlate with increased morbidity and mortality both in rat models of chronic
pulmonary inflammation and in human CF patients. It has previously been shown that
exoenzyme S is a potent stimulus for the proliferation of T cells in greater than 95% of adults, which could contribute to the pathogenesis of CF. The goal of this study was to determine the mechanism of T-cell stimulation by
exoenzyme S in an effort to shed light on the immune response and contribute to understanding its role in P. aeruginosa pathogenesis. The current studies demonstrate that
exoenzyme S stimulates naive T cells, since fetal blood lymphocytes proliferated and adult lymphocytes that expressed CD45RA proliferated. The percentage of T cells activated by
exoenzyme S after a 4-h culture (as measured by CD69 surface expression) was intermediate in magnitude compared to levels induced by a panel of
superantigens and
mitogens. To determine the mechanism of activation, the requirement for accessory cells was investigated. The proliferative response to
exoenzyme S was dependent on the presence of accessory cells but was not blocked by an anti-DR antibody.
Exoenzyme S activated both CD4(+) and CD8(+) T cells, but CD4(+) T cells were preferentially activated. The Vbeta repertoire of donor T cells showed no preferential activation or preferential expansion after stimulation by
exoenzyme S, suggesting that it is not a
superantigen. Taken together, our data suggest that
exoenzyme S is a T-cell
mitogen but not a
superantigen. Activation of a large percentage of T lymphocytes by
exoenzyme S may produce a lymphocyte-mediated inflammatory response that should be considered in the pathogenesis of CF.