Membrane lymphotoxin-α(2)β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist

In the early 1990s, it has been described that LTα and LTβ form LTα(2)β and LTαβ(2) heterotrimers, which bind to TNFR1 and LTβR, respectively. Afterwards, the LTαβ(2)–LTβR system has been intensively studied while the LTα(2)β–TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LTα(2)β–TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LTα. Here, we show that LTα(2)β interacts not only with TNFR1 but also with TNFR2. We furthermore demonstrate that membrane-bound LTα(2)β (memLTα(2)β), despite its asymmetric structure, stimulates TNFR1 and TNFR2 signaling. Not surprising in view of its ability to interact with TNFR2, LTα(2)β is inhibited by Etanercept, which is approved for the treatment of rheumatoid arthritis and also inhibits TNF and LTα.