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-κB is normally sequestered in the cytoplasm by members of the IκB family, including IκBα, IκBβ, and the recently cloned IκBɛ. Upon cellular activation, these inhibitors are rapidly phosphorylated on two amino-terminal serines, ubiquitinated, and degraded by the 26S proteasome, releasing a functional NF-κB. To determine the importance of IκBβ in NF-κB regulation in T cells, we generated transgenic mice expressing a constitutively active IκBβ mutant (mIκBβ) 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. mIκBβ is unable to totally displace IκBα from RelA-containing complexes, thus allowing a transient activation of NF-κB upon T-cell stimulation. However, mIκBβ completely blocks NF-κB activity after IκBα degradation. In addition, as a consequence of this inhibition, ikba expression is down regulated, along with that of other NF-κB-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, IκBβ cannot efficiently displace IκBα bound to RelA-containing complexes and that persistent NF-κB activity is required for proper T-cell responses in vivo.