Regulation of Peripheral Lymph Node Genesis by the Tumor Necrosis Factor Family Member Trance

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Abstract
Proper lymph node (LN) development requires tumor necrosis factor–related activation-induced cytokine (TRANCE) expression. Here we demonstrate that the defective LN development in TRANCE−/− mice correlates with a significant reduction in lymphotoxin (LT)αβ+α4β7+CD45+CD4+CD3− cells and their failure to form clusters in rudimentary mesenteric LNs. Transgenic TRANCE overexpression in TRANCE−/− mice results in selective restoration of this cell population into clusters, and results in full LN development. Transgenic TRANCE-mediated restoration of LN development requires LTαβ expression on CD45+ CD4+CD3− cells, as LNs could not be induced in LTα−/− mice. LTα−/− mice also showed defects in the fate of CD45+CD4+CD3− cells similar to TRANCE−/− mice. Thus, we propose that both TRANCE and LTαβ regulate the colonization and cluster formation by CD45+ CD4+CD3− cells in developing LNs, the degree of which appears to correlate with the state of LN organogenesis.