Activated T lymphocytes suppress osteoclastogenesis by diverting early monocyte/macrophage progenitor lineage commitment towards dendritic cell differentiation through down‐regulation of receptor activator of nuclear factor‐kappaB and c‐Fos

Summary Activated T lymphocytes either stimulate or inhibit osteoclastogenesis from haematopoietic progenitors in different experimental models. To address this controversy, we used several modes of T lymphocyte activation in osteoclast differentiation − mitogen‐pulse, anti‐CD3/CD28 stimulation and in vivo and in vitro alloactivation. Osteoclast‐like cells were generated from non‐adherent immature haematopoietic monocyte/macrophage progenitors in murine bone‐marrow in the presence of receptor activator of nuclear factor (NF)‐κB ligand (RANKL) and monocyte–macrophage colony‐stimulating factor (M‐CSF). All modes of in vivo and in vitro T lymphocyte activation and both CD4 + and CD8 + subpopulations produced similar inhibitory effects on osteoclastogenesis paralleled by enhanced dendritic cell (DC) differentiation. Osteoclast‐inhibitory effect was associated with T lymphocyte activation and not proliferation, and could be replaced by their culture supernatants. The stage of osteoclast differentiation was crucial for the inhibitory action of activated T lymphocytes on osteoclastogenesis, because the suppressive effect was visible only on early osteoclast progenitors but not on committed osteoclasts. Inhibition was associated specifically with increased granulocyte–macrophage colony‐stimulating factor (GM‐CSF) expression by the mechanism of progenitor commitment toward lineages other than osteoclast because activated T lymphocytes down‐regulated RANK, CD115, c‐Fos and calcitonin receptor expression, and increased differentiation towards CD11c‐positive DC. An activated T lymphocyte inhibitory role in osteoclastogenesis, confirmed in vitro and in vivo , mediated through GM‐CSF release, may be used to counteract activated bone resorption mediated by T lymphocyte‐derived cytokines in inflammatory and immune disorders. We also demonstrated the importance of alloactivation in osteoclast differentiation and the ability of cyclosporin A to abrogate T lymphocyte inhibition of osteoclastogenesis, thereby confirming the functional link between alloreaction and bone metabolism.