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⁺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.