Complementation of lymphotoxin alpha knockout mice with tumor necrosis factor-expressing transgenes rectifies defective splenic structure and function.
Lymphotoxin (LT)alpha knockout mice, as well as double LTalpha/tumor necrosis factor (TNF) knockout mice, show a severe splenic disorganization with nonsegregating T/B cell zones and complete absence of primary B cell follicles, follicular dendritic cell (FDC) networks, and germinal centers. In contrast, as shown previously and confirmed in this study, LTbeta-deficient mice show much more conserved T/B cell areas and a reduced but preserved capacity to form germinal centers and FDC networks. We show here that similar to the splenic phenotype of LTbeta-deficient mice, complementation of LTalpha knockout mice with TNF-expressing transgenes leads to a p55 TNF receptor-dependent restoration of B/T cell zone segregation and a partial preservation of primary B cell follicles, FDC networks, and germinal centers. Notably, upon lipopolysaccharide challenge, LTalpha knockout mice fail to produce physiological levels of TNF both in peritoneal macrophage supernatants and in their serum, indicating a coinciding deficiency in TNF expression. These findings suggest that defective TNF expression contributes to the complex phenotype of the LTalpha knockout mice, and uncover a predominant role for TNF and its p55 TNF receptor in supporting, even in the absence of LTalpha, the development and maintenance of splenic B cell follicles, FDC networks, and germinal centers.
Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece.
L
L
Alexopoulou
M
M
Pasparakis
G
G
Kollias
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D001402:B-Lymphocytes / Q000502:physiology*; D018858:Germinal Center; D006801:Humans; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D013154:Spleen / Q000166:cytology / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D019076:Transgenes; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
D015703:Antigens, CD; D008233:Lymphotoxin-alpha; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha