Proposed scheme of the initial activation of naive CD4⁺CD25⁺ T cells with allogeneic APCs and either IL-2 or IL-4, showing 2 separate activation pathways of CD4⁺CD25⁺ Tregs. We propose these be known as Ts1 and Ts2 cells, as they have distinct phenotypes, defined by the cytokines and cytokine receptors they express. Ts1 express IFN-γr, less IFN-γ, and more IL-5 than Ts2 cells, and Ts2 express IL-5rα and have greater IFN-γ mRNA induction. We hypothesize that expression of IFNγr or IL-5rα occurs as the Ts1 and Ts2 cells, respectively, become dependent on IFN-γ and IL-5 for survival and function as allo-Ag–specific Tregs.