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International Immunology Advance Access originally published online on January 11, 2008
International Immunology 2008 20(2):267-276; doi:10.1093/intimm/dxm144
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

No requirement for TRAIL in intrathymic negative selection

Erika Cretney1,*, Adam P. Uldrich1,*, Finlay W. McNab2, Dale I. Godfrey2,* and Mark J. Smyth1,*

1 Cancer Immunology Program, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia
2 Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia

Correspondence to: M. J. Smyth; E-mail: mark.smyth{at}petermac.org

The contribution of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway to intrathymic negative selection is a controversial subject with two studies suggesting a key role for TRAIL, while others demonstrated normal negative selection, in TRAIL- and TRAIL receptor-deficient mice. The basis of these discrepancies is unclear and may in part reflect differences in the negative selection models under investigation. Considering the importance of the negative selection process in the establishment of a competent immune system, it is essential that these discrepancies be fully resolved. In this study, we failed to identify a role for TRAIL in an acute model of peptide antigen-specific negative selection using a TCR transgenic system as well as antibody-mediated TCR/CD3 ligation in vitro and in vivo. Moreover, thymic dendritic cells, the main cellular mediators of negative selection in the thymus, did not constitutively express TRAIL, and TRAIL receptor (DR5) expression was negative or extremely low on thymocytes. Furthermore, in vitro thymocyte deletion was normal in C57BL/6 TRAIL–/– gld mice, suggesting that TRAIL and FasL do not function cooperatively to induce negative selection. These results, combined with the fact that aged C57BL/6 TRAIL–/– mice showed no signs of spontaneous autoimmunity, strongly indicate that intrathymic negative selection occurs normally in the absence of TRAIL signaling.

Keywords: apoptosis, autoimmune disease, negative selection, thymus, TRAIL

* These authors contributed equally to this study.

Transmitting editor: H. R. MacDonald

Received 5 September 2007, accepted 30 November 2007.


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