The immunoregulatory cytokine interleukin 10 (IL-10) is expressed mainly by T helper type 2 (T_H2) cells but also by T_H1 cells during chronic infection. Here we observed plasticity in the expression of IL-10 and IL-13 after chronic T_H1 stimulation; furthermore, the expression of Il10 and Il13 was regulated by the transcription factor E4BP4. Chronically stimulated E4BP4-deficient (Nfil3^−/−; called 'E4bp4^−/−' here) T_H1 cells, regulatory T cells (T_reg cells) and natural killer T cells (NKT cells) had attenuated expression of IL-10 and IL-13. Enforced expression of E4bp4 initiated the production of IL-10 and IL-13 by conventional T_H1 cells. E4bp4^−/− T_H2 cells showed impairment of IL-10 production with no effect on IL-13. Our results indicate that E4BP4 has multiple functions in controlling the plasticity of IL-13 in T_H1 cells and IL-10 in T_H1 cells, T_H2 cells, T_reg cells and NKT cells.