RANKL-Expressing Tregs drive bone erosion in rheumatoid arthritis and may serve as a marker for peripherally derived Tregs 2665

Abstract Description Rheumatoid arthritis (RA) is an autoimmune disease that leads to bone erosion via the RANK-RANKL axis, promoting osteoclast differentiation. A subset of T regulatory cells (Tregs) from inflamed joints expresses RANKL and accelerates bone erosion, but the roles of Treg RANKL are not fully understood. We generated mice with Tregs lacking RANKL (FoxP3YFP/cre RANKLflox/flox, hereafter TregΔRANKL). Subjected to K/BxN serum transfer arthritis, TregΔRANKL mice showed significantly reduced bone erosion versus WT (p = 0.003). Tregs activation markers (CD25, Foxp3, CD44, and CTLA-4) were higher in inflamed joints, with no difference between TregΔRANKL and WT. However, RANKL-expressing Tregs were elevated in synovial fluid versus lymph nodes in WT. Tregs from WT and TregΔRANKL mice displayed similar protein expression, cytokine production, and gene expression, and Tregs from both groups similarly mitigated colitis in RAG1-/- mice. At steady state less than 10% are RANKL-expressing Tregs increasing to 40% on in vitro-derived Tregs (iTregs) early in differentiation, suggesting RANKL may be expressed selectively in Tregs developed outside the thymus. Correspondingly, in gut tissues from Rag1-/- mice, Tregs arising from engrafted naïve T cells expressed high levels of RANKL, suggesting RANKL as a marker for peripherally derived Tregs (pTregs). Our findings confirm a pathogenic role of RANKL-expressing Tregs in RA-associated bone erosion and identify RANKL as a putative pTreg marker. Funding Sources NIAMS R01AR065538, NIH/NIAMS P30AR070253 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)