Osteoclast-Primed Foxp3+ CD8 T Cells Induce T-bet, Eomesodermin, and IFN-γ To Regulate Bone Resorption.
Osteoimmunology arose from the recognition that cytokines produced by lymphocytes can affect bone homeostasis. We have previously shown that osteoclasts, cells that resorb bone, act as APCs. Cross-presentation of Ags by osteoclasts leads to expression of CD25 and Foxp3, markers of regulatory T cells in the CD8 T cells. Octeoclast-induced Foxp3(+) CD25(+) regulatory CD8 T cells (OC-iTcREG) suppress priming of CD4 and CD8 T cells by dendritic cells. OC-iTcREG also limit bone resorption by osteoclasts, forming a negative feedback loop. In this study, we show that OC-iTcREG express concurrently T-bet and Eomesodermin (Eomes) and IFN-γ. Pharmacological inhibition of IκK blocked IFN-γ, T-bet, and Eomes production by TcREG Furthermore, we show, using chromatin immunoprecipitation, NF-κB enrichment in the T-bet and Eomes promoters. We demonstrate that IFN-γ produced by TcREG is required for suppression of osteoclastogenesis and for degradation of TNFR-associated factor 6 in osteoclast precursors. The latter prevents signaling by receptor activator of NF-κB ligand needed for osteoclastogenesis. Knockout of IFN-γ rendered TcREG inefficient in preventing actin ring formation in osteoclasts, a process required for bone resorption. TcREG generated in vivo using IFN-γ(-/-) T cells had impaired ability to protect mice from bone resorption and bone loss in response to high-dose receptor activator of NF-κB ligand. The results of this study demonstrate a novel link between NF-κB signaling and induction of IFN-γ in TcREG and establish an important role for IFN-γ in TcREG-mediated protection from bone loss.
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104; and.
Elena V
EV
Shashkova
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104; and.
Jahnavi
J
Trivedi
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104; and.
Anna B
AB
Cline-Smith
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104; and.
Chloe
C
Ferris
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104; and.
Zachary S
ZS
Buchwald
Division of Bone and Mineral Disease, Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110.
Jesse
J
Gibbs
Division of Bone and Mineral Disease, Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110.
Deborah
0000-0001-7101-5582
D
Novack
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104; and aurorar@slu.edu.
Rajeev
0000-0002-6609-6055
R
Aurora
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015153:Blotting, Western; D001862:Bone Resorption / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010010:Osteoclasts / Q000276:immunology*; D010012:Osteogenesis / Q000502:physiology; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000276:immunology; D000098815:T-bet Transcription Factor
C491198:Eomes protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016328:NF-kappa B; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma