DR3 Regulates Negative Selection during Thymocyte Development

Abstract

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.

ACKNOWLEDGMENTS

We thank J. Williamson for chromosome counting of ES cell clones, I. Rosewell and his group for microinjections and chimeric mouse breeding, P. Hagger and colleagues for breeding and maintenance of the DR3^−/− mouse colony, and P. Kieselow and H. von Boehmer for the kind gift of MAb T3.70.

This work was supported by the Imperial Cancer Research Fund. Eddie Wang was the recipient of a fellowship from the Beit Memorial Foundation for Medical Research, Anette Thern is a fellow of the Swedish Cancer Society, and Angela Denzel was the recipient of a Glaxo-Wellcome-BBSRC CASE Studentship.