DISTINCT ROLES FOR LYMPHOTOXIN-ALPHA AND TUMOR-NECROSIS-FACTOR IN ORGANOGENESIS AND SPATIAL-ORGANIZATION OF LYMPHOID-TISSUE

Specialized roles for the pro-inflammatory cytokines tumor necrosis fa ctor (TNF) and lymphotoxin (LT) were characterized in TNF/LT alpha(-/- ) and TNF-/- mice established by direct gene targeting of C57BL/6 ES c ells. The requirement for LT early in lymphoid tissue organogenesis is shown to be distinct from the more subtle and varied role of TNF in p romoting correct microarchitectural organization of leukocytes in LN a nd spleen. Development of normal Peyer's patch (PP) structure, in cont rast, is substantially dependent on TNF. Only mice lacking LT exhibit retarded B cell maturation in vivo and serum immunoglobulin deficienci es. A temporal hierarchy in lymphoid tissue development can now be def ined, with LT being an essential participant in general lymphoid tissu e organogenesis, developmentally preceeding TNF that has a more varied and subtle role in promotion of correct spatial organization of leuko cytes in LN and spleen. PP development in TNF-/- mice is unusual, indi cating that TNF is a more critical participant for this structure than it is for other lymphoid tissues.