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Molecular and Cellular Biology, January 2006, p. 668-677, Vol. 26, No. 2
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.2.668-677.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Normal Immune Development and Glucocorticoid-Induced Thymocyte Apoptosis in Mice Deficient for the T-Cell Death-Associated Gene 8 Receptor

Caius G. Radu,¹ Donghui Cheng,² Amar Nijagal,¹ Mireille Riedinger,² Jami McLaughlin,² Li V. Yang,² James Johnson,² and Owen N. Witte^1,2*

Department of Microbiology, Immunology and Molecular Genetics, University of California—Los Angeles,¹ Howard Hughes Medical Institute, University of California—Los Angeles, Los Angeles, California²

Received 2 September 2005/ Returned for modification 30 September 2005/ Accepted 19 October 2005

T-cell death-associated gene 8 (TDAG8) is a G-protein-coupled receptor transcriptionally upregulated by glucocorticoids (GCs) and implicated by overexpression studies in psychosine-mediated inhibition of cytokinesis and in GC-induced apoptosis. To examine the physiological function of TDAG8, we generated knockout (KO) mice by homologous recombination. An enhanced green fluorescent protein reporter was knocked into the disrupted tdag8 locus to allow the analysis of TDAG8 expression in living cells. Interestingly, we found that during thymocyte development, TDAG8 expression resembled the dynamic regulation described for known modulators of GC-induced apoptosis, including Bcl-2, Notch1, and GC receptor. TDAG8 was expressed in double-negative cells, was downregulated at the double-positive transition, and was upregulated in single-positive thymocytes. However, despite this striking expression pattern, maturation and selection of thymocytes, as well as major immune functions, were not affected in TDAG8 KO mice. In contrast to previous overexpression results, TDAG8 was dispensable for psychosine-induced formation of multinucleated cells. Furthermore, TDAG8 KO thymocytes showed normal apoptosis following in vivo and in vitro GC treatment. These results, while establishing a useful reporter strain to study T-lymphocyte maturation, argue against a critical role for TDAG8 in immune development, psychosine-mediated inhibition of cytokinesis, and GC-induced cell death.

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* Corresponding author. Mailing address: HHMI, University of California, Los Angeles, 675 Charles E. Young Dr. S, 5-748 MRL Bldg., Los Angeles, CA 90095-1662. Phone: (310) 206-0386. Fax: (310) 206-8822. E-mail: owenw{at}microbio.ucla.edu.

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Molecular and Cellular Biology, January 2006, p. 668-677, Vol. 26, No. 2
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.2.668-677.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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