The link between aberrant regulatory DC subset with breaking of tolerance in CD48 deficient mice (89.31)

Abstract

Dendritic cells (DCs) are antigen presenting cells with a dual role of priming T cells response and induction of peripheral tolerance. While CD11chigh DCs normally stimulate immunity (sDCs), CD11clowCD45rbhigh DCs were recently characterized as a regulatory subtype (rDC), which maintains low levels of costimulatory molecules after maturation. We found rDC levels were at least 2 times lower in bone marrow and spleens of CD48-/- C57BL/6 mice compared to their WT counterparts. Previously, we observed that aging CD48-/- mice developed spontaneous lupus-like autoimmune disease, indicated in elevated levels of autonuclear antibodies. We have shown that treatment of bone-marrow derived DCs with the neuropeptide, vasoactive intestinal peptide (VIP) and IL-10 strongly expanded the rDCs subtype, which produced high and low levels of IL-10 and IL-12, respectively. VIP-treated DCs of WT mice produced significantly higher amounts of IL-10, compared to CD48-/- DCs. We have also demonstrated that adoptive transfer of sDCs and rDCs subtypes together with OT-II-derived CD4+ T cells into WT and CD48-/- mice induced inhibition of OT-II-CD4+ T cell expansion only when WT-derived rDCs were transferred, as compared to expansion induced by their sDCs counterparts. These data suggest that dysfunctional and lower levels of rDCs of CD48-/- mice may be responsible for the development of spontaneous SLE in these mice when they are older.