Soluble Egg Antigen-Stimulated T Helper Lymphocyte Apoptosis and Evidence for Cell Death Mediated by FasL+T and B Cells during MurineSchistosoma mansoniInfection

Abstract

Granuloma formation around schistosomal eggs is induced by soluble egg antigens (SEA) and mediated by the activity of CD4⁺Th lymphocytes and their cytokines. Regulation of the inflammatory Th cell response during infection is still insufficiently understood. The hypothesis of this study was that activation-induced cell death (AICD) of CD4⁺T cells is involved in the immune inflammatory response. This study investigated the dynamics of splenic and granuloma CD4⁺Th cell apoptosis and Fas ligand (FasL) expression during the acute and chronic stages of murine schistosomal infection. Enhanced apoptosis of freshly isolated 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 but not granuloma 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. Coculture of purified splenic B cells with CD4⁺T cells and adoptive transfer of purified B cells indicated that antigen-stimulated B cells can kill CD4⁺Th cells. However, CD4⁺T cells were the dominant mediators of apoptosis in the granuloma. This study indicates that AICD is involved in the apoptosis of CD4⁺T cells during schistosomal infection.