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T cell activation causes the translocation of NF-kB dimers from the cytoplasm into the nucleus where NF-kB regulates inflammatory and immune response genes. Cbl-b is a negative regulator of T cell activation. However, the correlation between NF-kB activity and Cbl-b expression remains unclear. We showed that IKBαΔN-Tg T cells exhibited less NF-kB activity but higher levels of Cbl-b when compared with wild-type T cells. Furthermore, ursolic acid suppressed NF-kB activation and inhibited the downregulation of Cbl-b in wild-type T cells. NF-KBp65 specifically bound to an 11-bp NF-kB consensus sequence (gcaggaagtcc) in the Cbl-b promoter. Binding of NF-kB 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 IKBαΔN-Tg mice. These results indicated that NF-kB downregulated Cbl-b by binding and suppressing Cbl-b promoter in T cell activation. Our findings provide a novel role for NF-kB signaling in T cell activation. [ABSTRACT FROM AUTHOR]