(A) In normal Tregs, Itch controls the expression of GATA3 and phosphorylation of STAT6, which prevents Il4 gene transcription and IL-4 production. Thus, no Th2 cytokines (IL-4, IL-5, and IL-13) are produced or secreted by Itch-sufficient normal T cells; (B) In the absence of Itch, as evident in Itch^f/fFoxp3^Cre mice, Tregs cannot control GATA3 and STAT6, which results in increased GATA3 expression and STAT6 activation. Consequently, Il4 transcription is activated and IL-4 production is increased. IL-4 secreted by Itch-deficient Tregs instructs the normal naive CD4⁺ T cells to initiate a Th2 cell differentiation program for the secretion of large amounts of IL-4, IL-5, and IL-13, which together lead to uncontrolled Th2-type inflammation, especially in the lungs of Itch^f/fFoxp3^Cre mice. Red “X” indicates a block or deletion of the target molecules; black arrows indicate positive effects, and red lines indicate negative effects. Dotted line indicates no available evidence yet.