Il-1 Beta-Driven Osteoclastogenic Tregs Accelerate Bone Erosion In Arthritis

IL-1 beta is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1 beta contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn(-/-)), we observed that IL-1 beta blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4(+)Foxp3(+) Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn(-/-) Tregs and wild-type Tregs differentiated with IL-1 beta accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKL(hi)Foxp3(+) T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1 beta-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.