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AbstractIgM memory cells are recognized as an important component of B cell memory, based on several studies both in mice and humans. Our studies of B cells elicited in response to ehrlichial infection identified a population of CD11c/T-bet-positive IgM memory cells and an IgM T-bet-positive bone marrow antibody-secreting cell population (ASCs). The origin of these populations was unknown, although an early T-independent spleen CD11c-and T-bet-positive IgM plasmablast population precedes both, suggesting a linear relationship. The majority of IgM memory cells detected after day 30 post-infection had undergone somatic hypermutation, indicating that they expressed activation-induced cytidine deaminase (AID). Therefore, to identify early AID-expressing precursor cells, we infected an AID-regulated tamoxifen-inducible Cre-recombinase-EYFP reporter strain. Tamoxifen administration led to labeling of both the IgM memory cells and bone marrow ASCs on day 30 and later post-infection. High frequencies of labeled cells were identified on day 30 post-infection,following tamoxifen administration on day 10 post-infection. Both IgM memory cells and IgM bone marrow ASCs were labeled when tamoxifen was administered as early as day 4 post-infection. We also identified mechanisms involved in maintenance of the IgM bone marrow ASCs and IgM+ memory cells, namely proliferation and FcγRIIb respectively. BrdU studies revealed that the bone marrow IgM ASCs were maintained by proliferation, unlike the IgM memory cells. RNAseq analysis revealed a 2-fold higher expression of inhibitory Fc receptor, FcγRIIb. Because FcγRIIb inhibits B cell activation, we hypothesized that FcγRIIb negatively regulates IgM+ memory B cells by binding immune complexes present during low-level chronic infection. E. murisinfection of FcγRIIb-deficientmice revealed a 3-fold expansion of the IgM+ memory 30 days post-infection. We further demonstrated that the expansion of the IgM+ memory cells was not due to increased proliferation, but a decrease of apoptosis, due to a lack of Fas expression in FcγRIIb-deficient mice. This result was mimicked in AID-deficient mice, which lack the ability to class switch to IgG and make immune complexes, revealing a role for immune complexes in regulating IgM+ memory. Altogether, these studies demonstrate a novel germinal center-independent pathway for the generation of two distinct long-term IgM-positive B cell populations.
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