Role of I Kappa B Kinase Alpha and I Kappa B Kinase Beta in the Development and Function of B and T Lymphocytes

Abstract

Transcription factor NF-κB plays a key role in regulating the expression of genes involved in the control of the inflammatory and immune response. NF-κB binds to a group of inhibitory proteins, IκBs, in the cytoplasm of non-stimulated cells. Activation of NF-κB is regulated by the IκB kinase complex that phosphorylates IκB proteins, leading to their polyubiquitination and degradation. The released NF-κB molecules translocate into the nucleus and activate gene transcription. IκB kinase complex contains two catalytic subunits, IκB kinase α (IKKα) and IκB kinase β (IKKβ), and a regulatory subunit, IκB kinase γ (IKKγ) or NEMO. To evaluate the functions of IKKα and IKKβ in the development and function of the immune system, transgenic mice expressing dominant negative forms of IKKα and IKKβ specifically in their B cells or T cells were generated. Phenotypic analysis of transgenic mice expressing dominant negative IKKβ in the B cells revealed that the proliferation of B cells from these mutant mice in response to B cell mitogens was reduced due to impaired cell cycle progression. Accordingly, in vitro secretion of immunoglobulins by the mutant B cells in response to these mitogens was also decreased. In addition, these mice displayed selective defects in the production of specific immunoglobulin subclasses in response to type 2 but not type 1 T cell independent antigens. Moreover, the levels of certain immunoglobulin subclasses were reduced in mutant mice challenged with a T cell dependent antigen. These results indicate that IKKβ is critical for the proliferation of B cells and the control of some aspects of the humoral response. Transgenic mice expressing one or both of the dominant negative IKK specifically in T cells exhibited distinct phenotypes in thymocyte proliferation, cytokine production, and cell survival. Proliferation of thymic T cells from IKKβ mutant mice and IKKα/β mutant mice was markedly reduced due to impaired cell cycle progression. In addition, inhibition of both IKKα and IKKβ appeared to suppress the expression of multiple cytokines by thymocytes. Furthermore, apoptosis of the double positive thymocytes induced by the administration of anti-CD3 antibody was significantly reduced in transgenic mice expressing dominant negative IKKβ, but increased in mice expressing only dominant negative IKKα. These results indicate that IKKα and IKKβ play different roles in regulating the activation and survival of T cells.