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.
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 (LTalpha), and LTbeta 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-, LTalpha-, and LTbeta-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 LTbeta/TNF/LTalpha 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.
Kuprash
Dmitry V
DV
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. kuprash@online.ru
Alimzhanov
Marat B
MB
Tumanov
Alexei V
AV
Grivennikov
Sergei I
SI
Shakhov
Alexander N
AN
Drutskaya
Ludmila N
LN
Marino
Michael W
MW
Turetskaya
Regina L
RL
Anderson
Arthur O
AO
Rajewsky
Klaus
K
Pfeffer
Klaus
K
Nedospasov
Sergei A
SA
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D005786:Gene Expression Regulation; D018390:Gene Targeting; D007962:Leukocytes / Q000378:metabolism; D008221:Lymphoid Tissue / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008233:Lymphotoxin-alpha / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D005810:Multigene Family; D015398:Signal Transduction / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha