Uptake of apoptotic antigen-coupled cells by lymphoid dendritic cells and Cross-priming of CD8~+ T cells produced active immune unresponsiveness

摘要

The induction of immunologic unresponsiveness by i.v.admiistration of Ag-coupled lymphoid cells has been studied extensively,but the mechanisms remain unclear.We have further explored this model by examining the role of Fas/Fas ligand (FasL)-mediated apoptosis.Using i.v.injection of trinitrophenyl-coupled splenocytes (TNP-spl) as tolergoen,we found that Fas signaling for apoptosis in the spleen cells delivered by FasL in the recipient is the critical event.The requirement for Fas and FasL was overcome by prior induction of apoptosis in TNP-spl,making the tolergoen 100 times more potent.Prevention of apoptosis by a caspase inhbitor blocks tolerance.Interestingly,while blocking CD40/CD40 ligand interactioin does not prevent tolerance induction,an anonist anti-CD40 Ab turns tolergoenic TNP-slp into an immunizing Ag.Studies further showed that tolerance is induced through cross-presentation of Ag in a class I MHC-dependent manner by CD8~+CD11c~+ lymphoid-derived dendritic cells to regulatory T cells.The results provide a mechanism for a well-established method or inducing immunologic unresponsiveness.