Role of I Kappa B Kinase Alpha and I Kappa B Kinase Beta in the Development and Function of B and T Lymphocytes
Phenotypic analysis of transgenic mice expressing dominant negative IKKᠩn 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 IKKᠩs 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 IKKᠭutant mice and IKKa/ᠭutant mice was markedly reduced due to impaired cell cycle progression. In addition, inhibition of both IKKa and IKKᠡppeared 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 IKKᬠbut increased in mice expressing only dominant negative IKKa. These results indicate that IKKa and IKKᠰlay different roles in regulating the activation and survival of T cells.