Split peripheral tolerance: CD40 ligation blocks tolerance induction for CD8 T cells but not for CD4 T cells in response to intestinal antigens

The role of antigen-presenting cells in the balance between immunity and tolerance to intestinal antigens remains poorly understood. In this study, we examined whether CD40 ligation affects the induction of CD4 and CD8 T cell tolerance in response to intestinal antigens. We show that an agonistic anti-CD40 mAb treatment did not block the induction of OVA-specific CD4 T cell tolerance, whereas this approach enabled strong priming of OVA-specific cytotoxic T cells (CTL), preventing CTL tolerance to intestinal antigen. Such CTL priming was independent of CD4 T cell help but required B7 costimulation. Co-administration of anti-CD40 mAb increased the synthesis of IL-2 and the expression of CD25 by CD8 T cells, but neither IL-2 production nor CD25 expression by CD4 T cells was enhanced by anti-CD40 mAb. However, neutralization of TGF-beta together with addition of agonistic anti-CD40 mAb was able to reverse CD4 T cell tolerance. These findings suggest that the induction of tolerance versus immunity against intestinal antigens is determined by the status of the antigen-presenting cells and that signals via CD40 differently regulate the outcome of CD4 and CD8 T cells in vivo.