Osteoclast-Primed Foxp3+ CD8 T Cells Induce T-bet, Eomesodermin, and IFN-γ To Regulate Bone Resorption

Area of Science:

• Osteoimmunology
• Immunology
• Bone Biology

Background:

• Osteoimmunology explores cytokine effects on bone homeostasis.
• Osteoclasts function as antigen-presenting cells (APCs).
• Osteoclast-induced regulatory T cells (OC-iTcREG) suppress T cell priming and limit bone resorption.

Purpose of the Study:

• To investigate the molecular mechanisms by which OC-iTcREG regulate bone resorption.
• To determine the role of IFN-γ in OC-iTcREG-mediated suppression of osteoclastogenesis.

Main Methods:

• Analysis of OC-iTcREG expression of T-bet, Eomesodermin (Eomes), and IFN-γ.
• Pharmacological inhibition of IκK to assess its effect on TcREG cytokine production.
• Chromatin immunoprecipitation to detect NF-κB enrichment in T-bet and Eomes promoters.
• Assessment of osteoclastogenesis and actin ring formation in vitro and in vivo using IFN-γ knockout models.

Main Results:

• OC-iTcREG express T-bet, Eomes, and IFN-γ.
• Inhibition of IκK reduced IFN-γ, T-bet, and Eomes production.
• NF-κB was enriched in the T-bet and Eomes promoters.
• IFN-γ is essential for suppressing osteoclastogenesis by degrading TNFR-associated factor 6 and preventing actin ring formation.
• IFN-γ knockout TcREG failed to protect mice from bone loss induced by receptor activator of NF-κB ligand.

Conclusions:

• A novel link exists between NF-κB signaling and IFN-γ induction in TcREG.
• IFN-γ plays a critical role in TcREG-mediated protection against bone loss.
• This highlights a new regulatory pathway in osteoimmunology.