T cell activation causes the translocation of NF-kappa B dimers from the cytoplasm into the nucleus where NF-kappa B regulates inflammatory and immune response genes. Cbl-b is a negative regulator of T cell activation. However, the correlation between NF-kappa B activity and Cbl-b expression remains unclear. We showed that I kappa B alpha Delta N-Tg T cells exhibited less NF-kappa B activity but higher levels of Cbl-b when compared with wild-type T cells. Furthermore, ursolic acid suppressed NF-kappa B activation and inhibited the downregulation of Cbl-b in wild-type T cells. NF-kappa Bp65 specifically bound to an 11-bp NF-kappa B consensus sequence (gcaggaagtcc) in the Cbl-b promoter. Binding of NF-kappa B to this sequence suppressed Cbl-b transcription, thereby resulting in the negative regulation of Cbl-b expression. In addition, Cbl-b knockout led to the loss of cardiac allograft tolerance in I kappa B alpha Delta N-Tg mice. These results indicated that NF-kappa B downregulated Cbl-b by binding and suppressing Cbl-b promoter in T cell activation. Our findings provide a novel role for NF-kappa B signaling in T cell activation.