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 LT alpha/tumor necrosis factor (TNF) knockout mice, show a severe splenic disorganiza tion with nonsegregating T/B cell zones and complete absence of primar y B cell follicles, follicular dendritic cell (FDC) networks, and germ inal centers. In contrast, as shown previously and confirmed in this s tudy, LT beta-deficient mice show much more conserved T/B cell areas a nd a reduced but preserved capacity to form germinal centers and FDC n etworks. We show here that similar to the splenic phenotype of LT beta -deficient mice, complementation of LT alpha knockout mice with TNF-ex pressing transgenes leads to a p55 TNF receptor-dependent restoration of B/T cell zone segregation and a partial preservation of primary B c ell follicles, FDC networks, and germinal centers. Notably, upon lipop olysaccharide challenge, LTa knockout mice fail to produce physiologic al levels of TNF both in peritoneal macrophage supernatants and in the ir serum, indicating a coinciding deficiency in TNF expression. These findings suggest that defective TNF expression contributes to the comp lex phenotype of the LT alpha knockout mice, and uncover a predominant role for TNF and its p55 TNF receptor in supporting, even in the abse nce of LT alpha, the development and maintenance of splenic B cell fol licles, FDC networks, and germinal centers.