Regulation of peripheral lymph node genesis by the tumor necrosis factor family member TRANCE

Proper lymph node (LN) development requires tumor necrosis factor-related a ctivation-induced cytokine (TRANCE) expression Here we demonstrate that the defective LN development in TRANCE(-/-) mice con-elates with a significant reduction in lymphotoxin (LT)alpha beta (+)alpha (4)beta (+)(7)CD45(+)CD4( +)CD3(-) cells and their failure to form clusters in rudimentary mesenteric LNs. Transgenic TRANCE overexpression in TRANCE(-/-) mice results in selec tive restoration of this cell population into clusters, and results in full LN development. Transgenic TRANCE-mediated restoration of LN development r equires LT alpha beta expression on CD45(+) CD4+CD3- cells, as LNs could no t be induced in LT alpha (-/-) mice. LTa-/- mice also showed defects in the fate of CD45(+)CD4(+)CD3(-) cells similar to TRANCE(-/-) mice. Thus, we pr opose that both TRANCE and LT alpha beta regulate the colonization and clus ter formation by CD45(+) CD4(+)CD3(-) cells in developing LNs, the degree o f which appears to correlate with the state of LN organogenesis.