Proper lymph node (LN) development requires tumor necrosis factor–related activationinduced cytokine (TRANCE) expression. Here we demonstrate that the defective LN development in TRANCEJ/J mice correlates with a significant reduction in lymphotoxin (LT) ɑß+ ɑ4ß7+ CD45+CD4+CD3J cells and their failure to form clusters in rudimentary mesenteric LNs. Transgenic TRANCE overexpression in TRANCEJ/J 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 LTɑß expression on CD45+ CD4+CD3J cells, as LNs could not be induced in LTɑJ/J mice. LTɑJ/J mice also showed defects in the fate of CD45+CD4+CD3J cells similar to TRANCEJ/J mice. Thus, we propose that both TRANCE and LTɑß regulate the colonization and cluster formation by CD45+ CD4+CD3J cells in developing LNs, the degree of which appears to correlate with the state of LN organogenesis.