Cross-Presentation by Osteoclasts Induces FoxP3 in CD8+ T Cells

Abstract

Bone is remodeled throughout the life of an animal by the action of osteoclasts, which resorb bone, and osteoblasts, which form new bone. It has recently been recognized that T cells regulate osteoclasts by secreting a number of cytokines including type I and II IFNs and receptor activator of NF-kappaB ligand. In this study, we show that osteoclasts produce chemokines that recruit CD8(+) T cells. Using transgenic OT-I mice, we found that in the presence of OVA, osteoclasts induced the secretion of IL-2, IL-6, and IFN-gamma as well as the proliferation of CD8(+) T cells. CD8(+) T cells activated by osteoclasts expressed FoxP3, CTLA4, and receptor activator of NF-kappaB ligand. The FoxP3(+)CD8(+) T cells were anergic and suppressed dendritic cell priming of naive responder CD8(+) T cells. These results provide two novel observations for osteoimmunology: first, we demonstrate that osteoclasts can cross-present Ags to CD8(+) T cells. Second, these data show that osteoclasts are not only regulated by T cells, but they also can regulate T cells forming a feedback control loop. The induction of FoxP3 in T cells through a MHC class I-dependent manner provides a new mechanism to peripherally produce a regulatory T cell. These observations open a new avenue of investigation for the pathogenesis of autoimmune-mediated inflammatory bone diseases.