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.