Lymphotoxin (LT, LTα, TNFβ) is a member of the immediate TNF family that also includes TNF-α and lymphotoxin-β (LTβ). LT is produced by activated lymphocytes and functions as either a secreted homotrimer or a membrane-associated heterotrimer that includes the transmembrane protein LTβ. Secreted LTα 3 can bind to two cell surface receptors, TNFR1 and TNFR2, while the membrane-bound heterotrimer LTα 1 β 2 has been shown to interact with a distinct receptor, LTβR. LTα induces inflammation at the sites of expression of a rat insulin promoter-driven lymphotoxin (RIPLT) transgene in the pancreas and kidney. To determine the role of the various ligands and their receptors in LT-induced inflammation, mice deficient in either TNFR1, TNFR2, or LTβ were crossed to RIPLT-transgenic mice. Our results indicate that LTα-induced inflammation is dependent on the interaction of LTα 3 with TNFR1, and there is no obvious role for TNFR2, since in its absence, LTα-induced inflammation is quantitatively and qualitatively similar to that seen in the wild type. However, the absence of LTβ results in accentuated infiltration of the kidney with an increase in the proportion of memory cells in the infiltrate. These data show a crucial role for the secreted LTα 3 signaling via TNFR1 in LTα-induced inflammation, and a separate and distinct role for the membrane LTα 1 β 2 form in this inflammatory process.