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.
Kiesel
Jennifer R
JR
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
Buchwald
Zachary S
ZS
Aurora
Rajeev
R
D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis / Q000378:metabolism; D045142:Cross-Priming / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000145:classification / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism
D015415:Biomarkers; D018925:Chemokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D010047:Ovalbumin