Antigen-Specific Peripheral Tolerance Induced by Topical Application of NF-κB Decoy Oligodeoxynucleotide

Activation and maturation of dendritic cells (DC) are crucial for the establishment of delayed-type hypersensitivity (DTH). However, antigen presentation by immature DC (iDC) might lead to antigen-specific peripheral tolerance. NF-κB plays significant roles in upregulation of co-stimulatory molecules and cytokines in DC and therefore we investigated whether NF-κB decoy oligodeoxynucleotide (ODN) might induce tolerance to DTH. NF-κB decoy ODN suppressed ovalbumin (OVA)-induced DTH responses not only in naïve but also in presensitized mice. The suppressive effect was found to be antigen-specific. NF-κB decoy ODN-induced tolerance involved CD4+CD25+ regulatory T cells (Treg), because in vivo depletion of CD25+ T cells abrogated the tolerance, whereas adoptive transfer of such T cell population from tolerant mice induced tolerance. Furthermore, the induction of Treg was related to insufficient migration and/or maturation of DC, because a sizable DC population still remained in peripheral tissue even after exposure to exogenous antigen in NF-κB decoy ODN-treated mice. Even if they migrated into lymph nodes, they showed insufficient upregulation of co-stimulatory molecules and impaired antigen-specific activation of T cells. Topical application of NF-κB decoy ODN might thus be a new approach to induce antigen-specific peripheral tolerance.