Jun N-terminal kinase 2 modulates thymocyte apoptosis and T cell activation through c-Jun and nuclear factor of activated T cell (NF-AT)

The Jun N-terminal kinases (JNKs) recently have been shown to be required f or thymocyte apoptosis and T cell differentiation and/or proliferation. To investigate the molecular targets of JNK signaling in lymphoid cells, we us ed mice in which the serines phosphorylated by JNK in c-Jun were replaced b y homologous recombination with alanines (junAA mice). Lymphocytes from the se mice showed no phosphorylation of c-Jun in response to activation stimul i, whereas c-Jun was rapidly phosphorylated in wild-type cells. Despite the fact that c-jun is essential for early development, junAA mice develop nor mally; however, c-Jun N-terminal phosphorylation was required for efficient T cell receptor-induced and tumor necrosis factor-or-induced thymocyte apo ptosis, In contrast, c-Jun phosphorylation by JNK is not required for T cel l proliferation or differentiation. Because jnk2-/- T cells display a proli feration defect, we concluded that JNK2 must have other substrates required for lymphocyte function. Surprisingly, jnk2-/- T cells showed reduced NF-A T DNA-binding activity after activation. Furthermore, overexpression of JNK 2 in Jurkat T cells strongly enhanced NF-AT-dependent transcription. These results demonstrate that INK signaling differentially uses c-Jun and NF-AT as molecular effecters during thymocyte apoptosis and T cell proliferation.