IgM(+)IgD(-) B cells in human gut-associated lymphoid tissue have memory features and give rise to IgM(+) and IgA(+) antibody-secreting cells.

Human IgM(+) B cells vary in their surface levels of IgD, with the major circulating population of IgM(+)IgD(+) cells and a minor population (< 5%) of IgM(+)IgD(-) cells. In contrast, in gut-associated lymphoid tissue (GALT) derived from individuals undergoing tonsillectomy or appendectomy, IgM(+)IgD(-) B cells constitute ~ 30% of B cells. IgM(+)IgD(-) cells isolated from both tonsil and appendix lack plasma cell and B1 cell markers, and approximately 50% express the memory marker CD27. Functionally, GALT IgM(+)IgD(-) cells spontaneously secrete IgM, and class-switch to IgA in response to both T-dependent and T-independent stimulation ex-vivo. Immune repertoire profiling reveals that GALT IgM(+)IgD(-) cells exhibit lower levels of VH4-34 rearrangements, higher levels of somatic hypermutation, shorter CDR3 sequences and greater clonal overlap with switch memory cells than IgM(+)IgD(+) cells. Furthermore, clonal lineage analysis reveals that IgM(+)IgD(-) clones can include class-switched sequence variants. These findings suggest a maturational scheme starting from CD27(-)IgM(+)IgD(+) B cells to CD27(+)IgM(+)IgD(+), and then to CD27(-)IgM(+)IgD(-), and finally to CD27(+)IgM(+)IgD(-) B cells. In sum, IgM(+)IgD(-) B cells in the mucosa have memory features, give rise to class-switched memory B cells and antibody-secreting cells, and likely contribute significantly to the IgA repertoire in human GALT.