Interaction mechanism between teleost pIgR and IgM provides new insights on mucosal antibody evolution

Immunoglobulin M (IgM) plays a crucial role in both humoral and mucosal immunity, but its structure varies across vertebrate evolution. In mammals, transport of IgM across mucosal epithelia by the polymeric immunoglobulin receptor (pIgR) strictly depends on the joining chain (J-chain). However, in teleosts, IgM and pIgR can still interact in a J chain-independent manner, though the underlying mechanism remains unclear. Here, we elucidate a primordial, J-chain-independent interaction mechanism between pIgR and IgM in teleost fish. Structural and biochemical analyses show that teleost pIgR, comprising only two immunoglobulin-like domains (D1-D2), binds directly to the Cμ4 domain of tetrameric IgM via both D1 and D2. Notably, we reveal an unconventional 2:1 stoichiometry where one IgM tetramer engages two pIgR molecules. Two pIgR molecules bind to the IgM tetramer in an approximately symmetrical manner, yet the key amino acids involved in the interactions are not entirely identical. One pIgR molecule relies more heavily on its D1 domain for binding to the IgM tetramer, while the other molecule depends more on its D2 domain. Our finding contrasts sharply with the J-chain-dependent 1:1 complex in mammals, delineating an evolutionary difference between multivalent and monovalent pIgR-IgM engagement. Our results uncover a primordial mechanism of interaction mechanism between pIgR and IgM in teleost fish, and provide new insights into the co-evolution of IgM and pIgR.