Elevated Expression of Interleukin-7 Receptor in Inflamed Joints Mediates Interleukin-7-Induced Immune Activation in Rheumatoid Arthritis

Objective. To evaluate the expression and functional ability of the high-affinity interleukin-7 receptor (IL-7R alpha) in patients with rheumatoid arthritis (RA). Methods. Expression of IL-7R alpha and IL-7 was determined in synovial tissue from RA patients and was compared with that in synovial tissue from patients with undifferentiated arthritis (UA) and osteoarthritis (OA). IL-7Ra expression on CD4 T cells, CD19 B cells, and CD14 monocyte/macrophages from RA synovial tissue, synovial fluid, and peripheral blood was also assessed. The proliferative capacity of IL-7R alpha(bright) and IL-7R alpha(dim/-) T cells was measured. In addition, we examined IL-7R blockade with soluble human IL-7R alpha (hIL-7R alpha) in the prevention of immune activation of peripheral blood mononuclear cells. Results. We found significantly higher IL-7R alpha expression in RA and UA synovial tissue than in OA synovial tissue, and the level of IL-7Ra expression correlated significantly with the levels of CD3 and IL-7 expression. CD4 T cells from RA synovial fluid and synovial tissue strongly expressed IL-7Ra. A substantial percentage of B cells and macropbages from RA synovial fluid and synovial tissue also expressed IL-7R alpha, although less prominently than T cells. We found that peripheral blood IL-7R alpha(bright) T cells that did not express FoxP3 were highly proliferative as compared with IL-7R alpha(dim/-) T cells that did express high levels of FoxP3. Soluble hIL-7R alpha inhibited IL-7-induced proliferation and interferon-gamma production by mononuclear cells from RA patients. Conclusion. Our data suggest that enhanced expression of IL-7R alpha and IL-7 in RA patients contributes significantly to the joint inflammation by activating T cells, B cells, and macrophages. The inhibition of IL-7R-mediated immune activation by soluble hIL-7R alpha further indicates an important role of IL-7R alpha in inflammatory responses in RA, suggesting IL-7R alpha as a therapeutic target for immunotherapy in RA.