Cross-presentation by osteoclasts induces FoxP3 in CD8+ T cells.

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.