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

Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104

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-B 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- as well as the proliferation of CD8⁺ T cells. CD8⁺ T cells activated by osteoclasts expressed FoxP3, CTLA4, and receptor activator of NF-B 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.

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¹ Address correspondence and reprint requests to Dr. Rajeev Aurora, Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 South Grand Boulevard, DRC605, St. Louis, MO 63104. E-mail address: aurorar{at}slu.edu

² Abbreviations used in this paper: RANKL, receptor activator of NF-B ligand; RA, rheumatoid arthritis; sRANKL, soluble RANKL; DAPI, 4',6-diamidino-2-phenylindole; SDF-1, stromal cell-derived factor 1-; LDH, lactate dehydrogenase; DC, dendritic cell; TRAP, tartate-resistant acid phosphatase; T_REG, regulatory T cell; EAE, experimental autoimmune encephalomyelitis; MHC-I, MHC class I.

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