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(H)1 and T(H)2 effector cells. JNK activity observed in wild-type activated T-H cells was severely reduced in T-H cells from Jnk1(-/-) mice. The Jnk1(-/-) T cells hyperproliferated, exhibited decreased activation-induced cell death, and preferentially differentiated to T(H)2 cells. The enhanced production of T(H)2 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.