EFFECTS OF TUMOR-NECROSIS-FACTOR AND LYMPHOTOXIN ON PERIPHERAL LYMPHOID-TISSUE DEVELOPMENT

Previously, we have reported that neutralization of surface lymphotoxi n (LT-alpha beta) in mice which expressed an LT-beta receptor-Fc fusio n protein, driven by the cytomegalovirus promoter, resulted in an arra y of anatomic abnormalities. We now report that mice which express a t umor necrosis factor (TNF) receptor p60-Fc fusion protein (which neutr alizes TNF and soluble LT-alpha 3 activity) develop unique lymphoid ab normalities. Our data demonstrate that some aspects' of peripheral lym phoid organ development require both surface LT-alpha beta and TNF int eracting with their specific receptors, However, these related cytokin es are also capable of signaling distinct developmental events. Spleni c MAdCAM-1 expression, follicular dendritic cell localization and norm al Peyer's patch development all require both surface LT-alpha beta an d TNF activity. Marginal zone formation and splenic a cell localizatio n primarily require surface LT-alpha beta-LT-beta receptor interaction s. Primary follicle formation was dependent upon TNF receptor(s) engag ement. Interestingly spleen, lymph nodes and Peyer's patches from TNF receptor p60-Pc-expressing mice all develop different abnormalities, s uggesting distinct pathways of development in these lymphoid organs. T hymus development appears to be independent of these signaling pathway s. These results demonstrate that TNF and LT are crucial for normal pe ripheral, but not central lymphoid organ development.