An essential role for nuclear factor κB in promoting double positive thymocyte apoptosis

Abstract

To examine the role of nuclear factor (NF)-κB in T cell development and activation in vivo, we produced transgenic mice that express a superinhibitory mutant form of inhibitor κB-α (IκB-α(A32/36)) under the control of the T cell-specific CD2 promoter and enhancer (mutant [m]IκB-α mice). Thymocyte development proceeded normally in the mIκB-α mice. However, the numbers of peripheral CD8+ T cells were significantly reduced in these animals. The mIκB-α thymocytes displayed a marked proliferative defect and significant reductions in interleukin (IL)-2, IL-3, and granulocyte/macrophage colony-stimulating factor production after cross- linking of the T cell antigen receptor. Perhaps more unexpectedly, double positive (CD4+CD8+; DP) thymocytes from the mIκB-α mice were resistant to α-CD3-mediated apoptosis in vivo. In contrast, they remained sensitive to apoptosis induced by γ-irradiation. Apoptosis of wild-type DP thymocytes after in vivo administration of α-CD3 mAb was preceded by a significant reduction in the level of expression of the antiapoptotic gene, bcl-x(L). In contrast, the DP mIκB-α thymocytes maintained high level expression of bcl- x(L) after α-CD3 treatment. Taken together, these results demonstrated important roles for NF-κB in both inducible cytokine expression and T cell proliferation after TCR engagement. In addition, NF-κB is required for the α-CD3-mediated apoptosis of DP thymocytes through a pathway that involves the regulation of the antiapoptotic gene, bcl-x(L).