Membrane lymphotoxin-α₂β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist

In the early 1990s, it has been described that LTα and LTβ form LTα₂β and LTαβ₂ heterotrimers, which bind to TNFR1 and LTβR, respectively. Afterwards, the LTαβ₂-LTβR system has been intensively studied while the LTα₂β-TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LTα₂β-TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LTα. Here, we show that LTα₂β interacts not only with TNFR1 but also with TNFR2. We furthermore demonstrate that membrane-bound LTα₂β (memLTα₂β), despite its asymmetric structure, stimulates TNFR1 and TNFR2 signaling. Not surprising in view of its ability to interact with TNFR2, LTα₂β is inhibited by Etanercept, which is approved for the treatment of rheumatoid arthritis and also inhibits TNF and LTα.