Immunomodulatory effect of pneumolysin upon CD4 T cells
The human bacterial pathogen, Streptococcus pneumoniae (the pneumococcus), has been shown to modulate different parts of the innate immune response of its host, however its ability to modulate the adaptive immune response remains largely uninvestigated. Furthermore, the importance of the adaptive arm of the immune system in responding to Streptococcus pneumoniae has only recently begun to be elucidated. I therefore investigated a potentially novel pneumococcal immunomodulatory mechanism involving the effect of the pneumococcal toxin, pneumolysin, upon the cells at the heart of the adaptive immune response; the CD4 T cell. I generated purified pneumolysin and a purified pneumolysin mutant called F433 to allow me to examine this potential effect. I found that pneumolysin inhibits in vitro antigen specific murine CD4 T cell proliferation and cytokine production and that this effect is not observed with the F433 mutant pneumolysin. Furthermore, I demonstrated that pneumolysin accomplished this inhibitory activity by inducing apoptosis of activated CD4 T cells and suggest that lipid rafts may be involved in this process since we also demonstrated that pneumolysin preferentially binds to lipid rafts. Finally I demonstrated that pneumolysin is able to inhibit the in vivo accumulation of T cells and also inhibits in vivo antibody production. I propose that the immunomodulatory mechanism I have described may play an important role during pneumococcal infection and that this warrants further investigation. I propose that detailed in vivo studies are required to demonstrate that this mechanism functions during infection and to elucidate the effect this has upon the course of infection.