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-iTc(REG)) suppress priming of CD4 and CD8 T cells by dendritic cells. OC-iTc(REG) also limit bone resorption by osteoclasts, forming a negative feedback loop. In this study, we show that OC-iTc(REG) express concurrently T-bet and Eomesodermin (Eomes) and IFN-gamma. Pharmacological inhibition of I kappa K blocked IFN-gamma, T-bet, and Eomes production by Tc-REG. Furthermore, we show, using chromatin immunoprecipitation, NF-kappa B enrichment in the T-bet and Eomes promoters. We demonstrate that IFN-gamma produced by Tc-REG 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-kappa B ligand needed for osteoclastogenesis. Knockout of IFN-gamma rendered Tc-REG inefficient in preventing actin ring formation in osteoclasts, a process required for bone resorption. Tc-REG generated in vivo using IFN-gamma(-/-) T cells had impaired ability to protect mice from bone resorption and bone loss in response to high-dose receptor activator of NF-kappa B ligand. The results of this study demonstrate a novel link between NF-kappa B signaling and induction of IFN-gamma in Tc-REG and establish an important role for IFN-gamma in Tc-REG-mediated protection from bone loss.