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Molecular and Cellular Biology, December 2002, p. 8626-8634, Vol. 22, No. 24
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.24.8626-8634.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Redundancy in Tumor Necrosis Factor (TNF) and Lymphotoxin (LT) Signaling In Vivo: Mice with Inactivation of the Entire TNF/LT Locus versus Single-Knockout Mice

Dmitry V. Kuprash,1,2* Marat B. Alimzhanov,1,3,4 Alexei V. Tumanov,1,2 Sergei I. Grivennikov,1 Alexander N. Shakhov,2 Ludmila N. Drutskaya,2 Michael W. Marino,5 Regina L. Turetskaya,1,2 Arthur O. Anderson,6 Klaus Rajewsky,4 Klaus Pfeffer,3 and Sergei A. Nedospasov1,2*

Laboratory of Molecular Immunology, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, and Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia,1 Basic Research Program, SAIC Frederick, Inc., and Laboratory of Molecular Immunoregulation, Division of Basic Sciences, National Cancer Institute—Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201,2 Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, D-81675 Munich,3 Institute for Genetics, University of Cologne, D-50931 Cologne, Germany,4 Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, New York 10021,5 Department of Clinical Pathology, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland 21702-50116

Received 8 May 2002/ Returned for modification 2 July 2002/ Accepted 18 September 2002

Homologous genes and gene products often have redundant physiological functions. Members of the tumor necrosis factor (TNF) family of cytokines can signal activation, proliferation, differentiation, costimulation, inhibition, or cell death, depending on the type and status of the target cell. TNF, lymphotoxin {alpha} (LT{alpha}), and LTß form a subfamily of a larger family of TNF-related ligands with their genes being linked within a compact 12-kb cluster inside the major histocompatibility complex locus. Singly TNF-, LT{alpha}-, and LTß-deficient mice share several phenotypic features, suggesting that TNF/LT signaling pathways may regulate overlapping sets of target genes. In order to directly address the issue of redundancy of TNF/LT signaling, we used the Cre-loxP recombination system to create mice with a deletion of the entire TNF/LT locus. Mice with a triple LTß/TNF/LT{alpha} deficiency essentially manifest a combination of LT and TNF single-knockout phenotypes, except for microarchitecture of the spleen, where the disorder of lymphoid cell positioning and functional T- and B-cell compartmentalization is severer than that found in TNF or LT single-knockout mice. Thus, our data support the notion that TNF and LT have largely nonredundant functions in vivo.

* Corresponding author. Mailing address: Engelhardt Institute of Molecular Biology, 32 Vavilov St., 119991 Moscow, Russia. Phone: (7-905) 135-9964. Fax: (7-905) 135-1405. E-mail for Dmitry V. Kuprashi: kuprash{at}online.ru. E-mail for Sergei A. Nedospasov: snedos{at}online.ru.

Molecular and Cellular Biology, December 2002, p. 8626-8634, Vol. 22, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.24.8626-8634.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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