Interplay between TNF and Regulatory T Cells in a TNF-Driven Murine Model of Arthritis

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) are involved in several autoimmune diseases, including rheumatoid arthritis. TNF-alpha blockers induce therapeutic benefits in rheumatoid arthritis via a variety of mechanisms. We aimed to characterize the impact on Treg of TNF-alpha overexpression in vivo and of TNF-alpha inhibiting treatments. We used human TNF-alpha transgenic mice as a model of strictly TNF-alpha-dependent arthritis. Our study showed that initial Treg frequency was lower in TNF-alpha transgenic mice than in wild-type mice. However, the course of arthritis was marked by elevation of Treg frequency and a dramatic increase in expression of TNFR2. Antagonizing TNF-alpha with either the anti-human TNF-alpha Ab (infliximab) or active immunotherapy (TNF-kinoid) increased the Treg frequency and upregulated CTLA-4, leading to enhancement of suppressor activity. Moreover, both anti-TNF-alpha strategies promoted the differentiation of a CD62L(-) Treg population. In conclusion, in an in vivo model of TNF-alpha-driven arthritis, Treg frequency increased with inflammation but failed to control the inflammatory process. Both passive and active TNF-alpha-inhibiting strategies restored the suppressor activity of Treg and induced the differentiation of a CD62L(-) Treg population. The Journal of Immunology, 2011, 186: 3899-3910.