Osteoclast-primed Foxp3+ CD8 t cells induce t-bet, eomesodermin, and ifn-γ to regulate bone resorption

Elena V. Shashkova, Jahnavi Trivedi, Anna B. Cline-Smith, Chloe Ferris, Zachary S. Buchwald, Jesse Gibbs, Deborah Novack, Rajeev Aurora

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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-g. Pharmacological inhibition of IkK blocked IFN-g, T-bet, and Eomes production by TcREG. Furthermore, we show, using chromatin immunoprecipitation, NF-kB enrichment in the T-bet and Eomes promoters. We demonstrate that IFN-g 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-kB ligand needed for osteoclastogenesis. Knockout of IFN-g rendered TcREG inefficient in preventing actin ring formation in osteoclasts, a process required for bone resorption. TcREG generated in vivo using IFN-g2/2 T cells had impaired ability to protect mice from bone resorption and bone loss in response to high-dose receptor activator of NF-kB ligand. The results of this study demonstrate a novel link between NF-kB signaling and induction of IFN-g in TcREG and establish an important role for IFN-g in TcREG-mediated protection from bone loss.

Original languageEnglish
Pages (from-to)726-735
Number of pages10
JournalJournal of Immunology
Issue number3
StatePublished - Aug 1 2016

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