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Molecular and Cellular Biology, May 2001, p. 3451-3461, Vol. 21, No. 10
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.10.3451-3461.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

DR3 Regulates Negative Selection during Thymocyte Development

Eddie C. Y. Wang,1,dagger Anette Thern,1 Angela Denzel,1 Jeremy Kitson,2 Stuart N. Farrow,2 and Michael J. Owen1,*

Imperial Cancer Research Fund, Lincoln's Inn Fields, London WC2A 3PX,1 and Glaxo Wellcome, Stevenage, Herts SG1 2NY,2 United Kingdom

Received 16 October 2000/Returned for modification 6 December 2000/Accepted 22 February 2001

DR3 (Ws1, Apo3, LARD, TRAMP, TNFSFR12) is a member of the death domain-containing tumor necrosis factor receptor (TNFR) superfamily, members of which mediate a variety of developmental events including the regulation of cell proliferation, differentiation, and apoptosis. We have investigated the in vivo role(s) of DR3 by generating mice congenitally deficient in the expression of the DR3 gene. We show that negative selection and anti-CD3-induced apoptosis are significantly impaired in DR3-null mice. In contrast, both superantigen-induced negative selection and positive selection are normal. The pre-T-cell receptor-mediated checkpoint, which is dependent on TNFR signaling, is also unaffected in DR3-deficient mice. These data reveal a nonredundant in vivo role for this TNF receptor family member in the removal of self-reactive T cells in the thymus.

* Corresponding author. Mailing address: Imperial Cancer Research Fund, P.O. Box 123, Lincoln's Inn Fields, London, WC2A 3PX, United Kingdom. Phone: 44 020 7269 3069. Fax: 44 020 7269 3479 E-mail: m.owen{at}icrf.icnet.uk.

dagger Present address: Department of Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XX, United Kingdom.

Molecular and Cellular Biology, May 2001, p. 3451-3461, Vol. 21, No. 10
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.10.3451-3461.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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