Loss of immune tolerance caused by HTLV-I Tax. In healthy individuals, CD4⁺CD25⁺Foxp3⁺ Tregs suppress the proliferation of Teffs through (1) constitutive expression of Foxp3, and (2) induction of Foxp3 expression in Teffs (also known as infectious tolerance). However, in patients with HAM/TSP, HTLV-I Tax down-regulates TGF-βRII, which silences TGF-β–responsive genes such as foxp3. The resulting block in Foxp3 expression causes Tregs to lose suppressor function and causes Teffs to become resistant to TGF-β–inducible Foxp3 expression. The result is a breakdown in immune tolerance in patients with HAM/TSP characterized by expansion of potentially pathogenic CD4⁺ and CD8⁺ T cells and production of proinflammatory cytokines.