SURFACE LYMPHOTOXIN ALPHA BETA COMPLEX IS REQUIRED FOR THE DEVELOPMENT OF PERIPHERAL LYMPHOID ORGANS/

For more than a decade, the biological roles and the apparent redundan cy of the cytokines tumor necrosis factor (TNF) and lymphotoxin (LT) h ave been debated. LT alpha exists in its soluble form as a homotrimer, which like TNF only binds the TNF receptors, TNF-R55 or TNF-R75. The cell surface form of LT exists as a heteromer of LT alpha, and LT beta subunits and this complex specifically binds the LTP receptor (LT bet a-R). To discriminate the functions of the LT and TNF systems, soluble LT beta-R-immunoglobulin (Ig) or TNF-R-Ig fusion proteins were introd uced into embryonic circulation by injecting pregnant mice. Exposure t o LTP-R-Ig during gestation disrupted lymph node development and splen ic architecture in the progeny indicating that both effects are mediat ed by the surface LT alpha/beta complex. These data are the first to i dentify a cell surface ligand involved in immune organ morphogenesis. Moreover, they unambiguously discriminate the functions of the various TNF/LT ligands, provide a unique model to study compartmentalization of immune responses and illustrate the generic utility of receptor-Ig fusion proteins for dissecting/ordering ontogenetic events in the abse nce of genetic modifications.