The c-Jun NH₂-terminal kinase (JNK) signaling pathway has been implicated in the immune response that is mediated by the activation and differentiation of CD4 helper T (T_H) cells into T_H1 and T_H2 effector cells. JNK activity observed in wild-type activated T_H cells was severely reduced in T_H cells fromJnk1 ^–/– mice. TheJnk1 ^–/– T cells hyperproliferated, exhibited decreased activation-induced cell death, and preferentially differentiated to T_H2 cells. The enhanced production of T_H2 cytokines by Jnk1 ^–/– cells was associated with increased nuclear accumulation of the transcription factor NFATc. Thus, the JNK1 signaling pathway plays a key role in T cell receptor–initiated T_H cell proliferation, apoptosis, and differentiation.