DCs in Immune Tolerance in Steady-State Conditions

Dendritic cells (DCs) are antigen-presenting cells (APCs) characterized by a unique capacity to stimulate na�ve T cells and initiate primary immune responses. Recent studies suggest that DCs are also involved in the induction of immunological tolerance in peripheral tissues under steady-state conditions by maintaining the homeostasis of self-reactive CD4⁺ Foxp3⁺ naturally occurring thymic-derived regulatory T cells (nT_regs ) and de novo generation of antigen-specific CD4⁺ Foxp3⁺ inducible regulatory T cells (iT_regs ). We demonstrate here the impact of CD11⁺ DCs on the antigen-specific differentiation of CD4⁺ Foxp3⁺ iT_regs from CD4⁺ Foxp3⁻ T cells under steady-state and inflammatory conditions. CD11c⁺ DCs promoted the transforming growth factor (TGF)-β1-mediated conversion of CD4⁺ Foxp3⁻ T cells into CD4⁺ Foxp3⁺ iT_regs in vitro, while stimulation of CD11c⁺ DCs with CpG oligodeoxynucleotide (ODN) abrogated this conversion. Furthermore, antigen-specific generation of CD4⁺ Foxp3⁺ iT_regs required the function of CD11⁺ DCs under steady-state conditions, whereas such conversion was severely abolished under inflammatory conditions. Thus, these results suggest the crucial role of DCs in the antigen-specific de novo conversion of CD4⁺ Foxp3⁻ T cells into CD4⁺ Foxp3⁺ iT_regs under steady-state conditions, thereby leading to the establishment of peripheral immune tolerance.