EXPRESSION OF CONSTITUTIVELY ACTIVE I-KAPPA-B-BETA IN T-CELLS OF TRANSGENIC MICE - PERSISTENT NF-KAPPA-B ACTIVITY IS REQUIRED FOR T-CELL IMMUNE-RESPONSES

The transcription factor NF-kappa B is normally sequestered in the cyt oplasm by members of the I kappa B family, including I kappa B alpha, I kappa B beta, and the recently cloned I kappa B epsilon. Upon cellul ar activation, these inhibitors are rapidly phosphorylated on two amin o-terminal serines, ubiquitinated, and degraded by the 26S proteasome, releasing a functional NF-kappa B. To determine the importance of I k appa B beta in NF-kappa B regulation in T cells, we generated transgen ic mice expressing a constitutively active I kappa B beta mutant (mI k appa B beta) under the control of the lck promoter. The transgene cont ains the two critical N-terminal serine residues mutated to alanines a nd therefore no longer susceptible to degradation upon cell activation . mI kappa B beta is unable to totally displace I kappa B alpha from R elA-containing complexes, thus allowing a transient activation of NF-k appa B upon T-cell stimulation. However, mI kappa B beta completely bl ocks NF-kappa B activity after I kappa B alpha degradation. In additio n, as a consequence of this inhibition, ikba expression is down regula ted, along with that of other NF-kappa B-regulated genes. These transg enic mice have a significant reduction in the peripheral T-cell popula tion, especially CD8(+) cells. The remaining T cells have impaired pro liferation in response to phorbol 12-myristate 13-acetate plus phytohe magglutinin or calcium ionophore but not to anti-CD3/anti-CD28 costimu lation. As a result of these alterations, transgenic animals present d efects in immune responses such as delayed-type hypersensitivity and t he generation of specific antibodies against T-cell-dependent antigens . These results show that in nonstimulated T cells, I kappa B beta can not efficiently displace I kappa B alpha bound to RelA-containing comp lexes and that persistent NF-kappa B activity is required for proper T -cell responses in vivo.