Figure 3.

Osteoclasts induce tolerogenic Tc_REG. This figure summarizes how OC induce Tc_REG to promote restore homeostasis under inflammatory conditions. OC use three signals: antigen-loaded MHC I that ligates TCR on CD8 T-cells, CD200 (a costimulation molecule that activates NF-κB) and the Notch ligand DLL4 that engages Notch1 and Notch4 on the T-cells. TNFα and/or IL-17A downregulate DLL4 expression on OC. Treatment with pRANKL leads to increased expression DLL4. Tc_REG secrete IFN-γ that suppress osteoclastogenesis by degrading TRAF6 and also suppress resorption by mature OC. Tc_REG also secrete IL-10, which is required for the bone anabolic activity but not resolution of inflammation. IL-10 may also target Ocy to improve cortical bone mass. Resolution of inflammation appears to be mediated by CTLA4 expressed on Tc_REG.