Itch is an E3 ubiquitin ligase that is disrupted in nonagouti-lethal or itchy mice. Itch deficiency leads to severe immune and inflammatory disorders and constant itching of the skin. Here we show that Itch^−/− T cells show an activated phenotype and enhanced proliferation. Production of the type 2 T helper (T_H2) cell cytokines interleukin 4 (IL-4) and IL-5 by Itch^−/− T cells was augmented upon stimulation, and the T_H2-dependent serum concentrations of immunoglobulin G1 (IgG1) and IgE in itchy mice were also increased. Molecularly, Itch associated with and induced ubiquitination of JunB, a transcription factor that is involved in T_H2 differentiation. These results provide a molecular link between Itch deficiency and the aberrant activation of immune responses in itchy mice.