Operational feedback loops involving direct effects of TNF on CD25⁺Tregs enhance diseased states in RA. Diseased states in RA are established and stabilized though negative feedback of TNF directly on TGFβ-induced CD25⁺Tregs. It is likely that in both populations intrinsic Tregs, as well as adaptively induced Tregs, can be affected. In many individuals, anti-TNF therapy can re-establish the equilibrium present in healthy individuals. Illustration by Kenneth Probst.