The Journal of Experimental Medicine
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Published 16 June 2003. doi:10.1084/jem.20030141
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© Rockefeller University Press, 0022-1007/2003/6/1623 $5.00
The Journal of Experimental Medicine, Volume 197, Number 12, 1623-1633

NIK-dependent RelB Activation Defines a Unique Signaling Pathway for the Development of V{alpha}14i NKT Cells

Dirk Elewaut1,2, Raziya B. Shaikh1,3, Kirsten J. L. Hammond1, Hilde De Winter1, Andrew J. Leishman4, Stephane Sidobre1, Olga Turovskaya1, Theodore I. Prigozy5, Lisa Ma2, Theresa A. Banks2, David Lo6, Carl F. Ware2,3, Hilde Cheroutre1 and Mitchell Kronenberg1,3

1 Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
2 Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
3 Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093
4 PPL Therapeutics, Roslin, Edinburgh, EH25 9PP Scotland, United Kingdom
5 Tampa Bay Research Institute, St. Petersburg, FL 33716
6 Digital Gene Technologies, La Jolla, CA 92037

Address correspondence to Dr. Mitchell Kronenberg, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121. Phone: 858-678-4540; Fax: 858-678-4595; E-mail: mitch{at}liai.org

A defect in RelB, a member of the Rel/nuclear factor (NF)-{kappa}B family of transcription factors, affects antigen presenting cells and the formation of lymphoid organs, but its role in T lymphocyte differentiation is not well characterized. Here, we show that RelB deficiency in mice leads to a selective decrease of NKT cells. RelB must be expressed in an irradiation-resistant host cell that can be CD1d negative, indicating that the RelB expressing cell does not contribute directly to the positive selection of CD1d-dependent NKT cells. Like RelB-deficient mice, aly/aly mice with a mutation for the NF-{kappa}B–inducing kinase (NIK), have reduced NKT cell numbers. An analysis of NK1.1 and CD44 expression on NKT cells in the thymus of aly/aly mice reveals a late block in development. In vitro, we show that NIK is necessary for RelB activation upon triggering of surface receptors. This link between NIK and RelB was further demonstrated in vivo by analyzing RelB+/- x aly/+ compound heterozygous mice. After stimulation with {alpha}-GalCer, an antigen recognized by NKT cells, these compound heterozygotes had reduced responses compared with either RelB+/- or aly/+ mice. These data illustrate the complex interplay between hemopoietic and nonhemopoietic cell types for the development of NKT cells, and they demonstrate the unique requirement of NKT cells for a signaling pathway mediated by NIK activation of RelB in a thymic stromal cell.

Key Words: T lymphocytes • NF-{kappa}B • lymphocyte development • lipid antigens • CD1


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