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

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(+)α(4)β(7) (+)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.