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An Essential Role for Nuclear Factor B in Promoting Double Positive Thymocyte Apoptosis

Thore Hettmann^*, Joseph DiDonato, Michael Karin, and Jeffrey M. Leiden^*

From the ^* Departments of Medicine and Pathology, University of Chicago, Chicago, Illinois 60637; and the Department of Pharmacology, University of California San Diego, San Diego, California 92093

To examine the role of nuclear factor (NF)-B in T cell development and activation in vivo, we produced transgenic mice that express a superinhibitory mutant form of inhibitor B- (IB-_A32/36) under the control of the T cell–specific CD2 promoter and enhancer (mutant [m]IB- mice). Thymocyte development proceeded normally in the mIB- mice. However, the numbers of peripheral CD8⁺ T cells were significantly reduced in these animals. The mIB- 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 mIB- mice were resistant to -CD3–mediated apoptosis in vivo. In contrast, they remained sensitive to apoptosis induced by -irradiation. Apoptosis of wild-type DP thymocytes after in vivo administration of -CD3 mAb was preceded by a significant reduction in the level of expression of the antiapoptotic gene, bcl-x_L. In contrast, the DP mIB- thymocytes maintained high level expression of bcl-x_L after -CD3 treatment. Taken together, these results demonstrated important roles for NF-B in both inducible cytokine expression and T cell proliferation after TCR engagement. In addition, NF-B is required for the -CD3–mediated apoptosis of DP thymocytes through a pathway that involves the regulation of the antiapoptotic gene, bcl-x_L.

Key Words: nuclear factor B • inhibitor B-_A32/36 • thymocytes • apoptosis • bcl-x_L

Thore Hettmann is a Terry Fox Research Fellow. This work was supported in part by a grant from the NIAID to J.M. Leiden (2 R37 A129637-07) and by the Cancer Center of the University of Chicago, and by a grant from the NIAID to M. Karin (R01 AI43477-01).

Abbreviations used: EMSA, electrophoretic mobility shift assay; FTOC, fetal thymic organ culture; HA, hemagglutinin; IB-, inhibitor B-; mIB-, mutant IB-; NF-B, nuclear factor B; TUNEL, Tdt-mediated dUTP nick end labeling.

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