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 redundancy of the cytokines tumor necrosis factor (TNF) and lymphotoxin (LT) have 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 LT beta receptor (LT beta-R). To discriminate the functions of the LT and TNF systems, soluble LT beta-R-immunoglobulin (Ig) or TNF-R-Ig fusion proteins were introduced into embryonic circulation by injecting pregnant mice. Exposure to LT beta-R-Ig during gestation disrupted lymph node development and splenic architecture in the progeny indicating that both effects are mediated by the surface LT alpha/beta complex. These data are the first to identify 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 absence of genetic modifications.
Rennert
P D
PD
Biogen Inc., Cambridge, Massachusetts 02142, USA.
Browning
J L
JL
Mebius
R
R
Mackay
F
F
Hochman
P S
PS
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D007074:Immunoglobulin G / Q000494:pharmacology; D008198:Lymph Nodes / Q000196:embryology; D008221:Lymphoid Tissue / Q000196:embryology*; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009024:Morphogenesis; D010581:Peyer's Patches / Q000196:embryology; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013154:Spleen / Q000196:embryology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007074:Immunoglobulin G; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha