Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals

Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut-specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell-independent or T cell-dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus-embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA-only-coated or uncoated bacteria. Thus, SIgM may emerge from pre-existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities to mucus.Supported by European Advanced Grant (ERC-2011-ADG-20110310), MINECO (SAF2014-52483-R), AGAUR (2014 SGR 832), US NIH grants P01 AI61093, R01 AI57653, and U01 AI95613 (to A.C.), Boeringher Ingelheim grant 134564-2 (to A.C.), NIH grant R01 DK 112296-01 (to A.C. and S.M.), and Fondo de Investigación Sanitaria ISCIII fellowships CD14/00060 and CM13/00136 (to G.M. and L.C., respectively)