| Granuloma formation around schistosomal eggs is induced by soluble egg antigens (SEA) and mediated by the activity of CD4+ Th lymphocytes and their cytokines. The hypothesis of this study was that activation-induced cell death (AICD) of CD4+ T cells was involved in regulating the immune inflammatory response. The dynamics of splenic and granuloma CD4 + Th cell apoptosis and Fas ligand (FasL) expression was studied. Enhanced apoptosis of CD4+ Th lymphocytes commenced after egg deposition and persisted during the peak and modulated phases of granuloma formation. After oviposition, CD4+, CD8+ and CD19+ splenocytes and granuloma cells expressed elevated levels of FasL, but FasL expression declined during the downmodulated stage of infection. In culture, SEA induced splenic and granuloma CD4+ T cell apoptosis and stimulated expression of FasL on splenic CD4+ T cells, CD8+ T cells and CD19+ B cells. SEA-stimulated splenocytes and granuloma cells preferentially lysed a Fas-transfected target cell line. Depletion of B cells from SEA-stimulated splenic cultures decreased CD4+ T cell apoptosis. CD4+ T cells were the dominant mediators of apoptosis in the granuloma. Co-culture of purified splenic B cells with CD4+ T cells and adoptive transfer of purified B cells indicated that antigen-stimulated B cells induce apoptosis of CD4 + Th cells. FasL expression by splenic CD19+ cells required CD4+ T cell help. The requirement for CD4+ T cells could be replaced by culture supernatants from SEA-stimulated splenocytes. Anti-IL-10 and anti-IL-4 antibodies inhibited the supernatant-stimulated FasL expression. Culture of purified B cells with rIL-4, rIL-10 and SEA led to high expression of FasL on B-1a cells but not on B-2 cells. B-1a cells displayed constitutive surface expression of FasL compared with B-2 cells. Infection with S. mansoni induced surface FasL expression on both subsets of B cells following egg deposition. Purified B-1 a cells from uninfected and 8wks infected mice were potent effectors of in vitro CD4+ T cell apoptosis. CD4+ T cell apoptosis was impaired in schistosome-infected, B cell deficient mice. These results suggest that schistosome infection induces B cells that mediate AICD of CD4+ T cells. |
