Suppression of mature dendritic cell function by regulatory T cells in vivo is abrogated by CD40 licensing

The priming of CD4(+) effector T cells (T(eff)) in vivo is induced by mature dendritic cells (DC) and controlled by CD4(+)CD25(+)Foxp3(+) regulatory T cells (T(reg)). It remains unclear,however, how T(eff) priming vs T(reg) suppression are regulated during Ag presentation by DC in secondary lymphoid organs at the simultaneous presence of T(eff) and T(reg). In this study, we used an peptide-specific DO11.10 TCR-transgenic adoptive transfer model to follow the T(eff) priming kinetics and the mechanisms of suppression by T(reg). T(reg) activation was slower as compared with T(eff) and could not influence the early T(eff) expansion but limited the T(eff) response leading to lower T(eff) numbers in the memory phase. DC-T(reg) cell contacts remained unaltered during suppression by T(reg) and led to a down-regulation of the costimulatory molecules CD80, CD86, PD-L1, and PD-L2 but not MHC II, CD40, ICOS-L, or CD70 from the mature DC surface. This effect was observed only after DC maturation with TNF or LPS but not after additional CD40 licensing. Together, our data indicate that Treg suppression against nonself Ags in vivo occurs delayed due to the slower Treg response, is mediated to a large extent through DC modulation, but is controlled by the type of DC maturation.