Figure 5.

Model of CD4⁺ and CD8⁺ T-cell effects on osteoclastic bone resorption. Homeostatic reconstitution of CD4⁺ T cells leads to production of both tumor necrosis factor (TNF) and receptor activator of nuclear factor κB ligand (RANKL) in the bone marrow microenvironment. TNF amplified RANKL activity and promoted additional RANKL production by osteoblast-lineage cells, driving cortical and trabecular bone loss. CD8⁺ T cells produce only TNF in the bone marrow, inducing relatively modest levels of RANKL from osteoblasts and driving trabecular bone loss only. In addition, reconstitution of CD4⁺ T cells further leads to reinitiating of adaptive immune responses, including humoral immunity and antigen-presentation activity, that lead to additional TNF production by B cells and other antigen-presenting cells (APCs), such as macrophages. This potent inflammatory activity of CD4⁺ T cells likely drives a critical threshold of RANKL and TNF that is capable of driving cortical bone resorption. TNFR1, TNF receptor 1.