The tumor necrosis factor (TNF) family cytokines lymphotoxin (LT) ␣ and LT␤ form heterotrimers that are expressed on the surface of activated lymphocytes and natural killer cells; LT␣ homotrimers can be secreted as well. Mice with a disrupted LT␣ gene lack lymph nodes (LN), Peyer's patches (PP), and follicular dendritic cell (FDC) networks and reveal profound defects of the splenic architecture. However, it is unclear which of these abnormalities is the result of the absence in LT␣ homotrimers or LT␣␤ heterotrimers. To distinguish between these two possibilities, a mouse strain deficient in LT␤ was created employing Cre͞ loxP-mediated gene targeting. Mice deficient in LT␤ reveal severe defects in organogenesis of the lymphoid system similar to those of LT␣ ؊͞؊ mice, except that mesenteric and cervical LN are present in most LT␤-deficient mice. Both LT␤-and LT␣-deficient mice show significant lymphocytosis in the circulation and peritoneal cavity and lymphocytic infiltrations in lungs and liver. After immunization, PNA-positive B cell clusters were detected in the splenic white pulp of LT␤-deficient mice, but FDC networks were severely underdeveloped. Collectively, these results indicate that LT␣ can signal independently from LT␤ in the formation of PNA-positive foci in the spleen, and especially in the development of mesenteric and cervical LN.

Tumor necrosis factor (TNF, TNFalpha) is implicated in various pathophysiological processes and can be either protective, as in host defense, or deleterious, as in autoimmunity or toxic shock. To uncover the in vivo functions of TNF produced by different cell types, we generated mice with TNF ablation targeted to various leukocyte subsets. Systemic TNF in response to lipopolysaccharide was produced mainly by macrophages and neutrophils. This source of TNF was indispensable for resistance to an intracellular pathogen, Listeria, whereas T-cell-derived TNF was important for protection against high bacterial load. Additionally, both T-cell-derived TNF and macrophage-derived TNF had critical and nonredundant functions in the promotion of autoimmune hepatitis. Our data suggest that T-cell-specific TNF ablation may provide a therapeutic advantage over systemic blockade.