Expression of constitutively active IκBβ in T cells of transgenic mice:: Persistent NF-κB activity is required for T-cell immune responses

The transcription factor NF-kappa B is normally sequestered in the cytoplasm 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 cellular activation, these inhibitors are rapidly phosphorylated on two amino-terminal serines, ubiquitinated, and degraded by the 26S proteasome, releasing a functional NF-kappa B. To determine the importance of I kappa B beta in NF-kappa B regulation in T cells, we generated transgenic mice expressing a constitutively active I kappa B beta mutant (mI kappa B beta) under the control of the lck promoter. The transgene contains the two critical N-terminal serine residues mutated to alanines and therefore no longer susceptible to degradation upon cell activation. mI kappa B beta is unable to totally displace I kappa B alpha from RelA-containing complexes, thus allowing a transient activation of NF-kappa B upon T-cell stimulation. However, mI kappa B beta completely blocks NF-kappa B activity after I kappa B alpha degradation. In addition, as a consequence of this inhibition, ikba expression is down regulated, along with that of other NF-kappa B-regulated genes. These transgenic mice have a significant reduction in the peripheral T-cell population, especially CD8(+) cells. The remaining T cells have impaired proliferation in response to phorbol 12-myristate 13-acetate plus phytohemagglutinin or calcium ionophore but not to anti-CD3/anti-CD28 costimulation. As a result of these alterations, transgenic animals present defects in immune responses such as delayed-type hypersensitivity and the generation of specific antibodies against T-cell-dependent antigens. These results show that in nonstimulated T cells, I kappa B beta cannot efficiently displace I kappa B alpha bound to RelA-containing complexes and that persistent NF-kappa B activity is required for proper T-cell responses in vivo.