Perturbation of the T Lymphocyte Lineage In Transgenic Mice Expressing a Constitutive Repressor of Nuclear Factor (NF)-κB

• DOI: 10.1084/jem.185.11.1897
• Publication Date: 2002-07-26T16:49:30Z
• Authors: Mark R. Boothby; Ana L. Mora; David C. Scherer; Jeffrey A. Brockman; Dean W. Ballard
• Keywords: CD4-Positive T-Lymphocytes; 0301 basic medicine; Immunoblotting; NF-kappa B; Receptors, Antigen, T-Cell; Apoptosis; Mice, Transgenic; CD8-Positive T-Lymphocytes; Flow Cytometry; Proto-Oncogene Proteins c-rel; DNA-Binding Proteins; Mice; 03 medical and health sciences; NF-KappaB Inhibitor alpha; Proto-Oncogene Proteins; Animals; Interleukin-2; Cell Lineage; Electrophoresis, Polyacrylamide Gel; I-kappa B Proteins; Cell Division; Signal Transduction

Members of the nuclear factor (NF)-κB/Rel family transcription factors are induced during thymic selection and in mature T lymphocytes after ligation of the T cell antigen receptor (TCR). Despite these findings, disruption of individual NF-κB/Rel genes has revealed no intrinsic defect in the development of mature T cells, perhaps reflecting functional redundancy. To circumvent this possibility, the T cell lineage was targeted to express a trans-dominant form of IκBα that constitutively represses the activity of multiple NF-κB/Rel proteins. Transgenic cells expressing this inhibitor exhibit a significant proliferative defect, which is not reversed by the addition of exogenous interleukin-2. Moreover, mitogenic stimulation of splenocytes leads to increased apoptosis of transgenic T cells as compared with controls. In addition to deregulated T cell growth and survival, transgene expression impairs the development of normal T cell populations as evidenced by diminished numbers of TCRhi CD8 single-positive thymocytes. This defect was significantly amplified in the periphery and was accompanied by a decrease in CD4+ T cells. Taken together, these in vivo findings indicate that the NF-κB/Rel signaling pathway contains compensatory components that are essential for the establishment of normal T cell subsets.