T-Bet+ IgM Memory Cells Generate Multi-lineage Effector B Cells.

Immunoglobulin M (IgM) memory cells undergo differentiation in germinal centers following antigen challenge, but the full effector cell potential of these cells is unknown. We monitored the differentiation of enhanced yellow fluorescent protein (eYFP)-labeled CD11c+ and CD11cneg T-bet+ IgM memory cells after their transfer into naive recipient mice. Following challenge infection, many memory cells differentiated into IgM-producing plasmablasts. Other donor B cells entered germinal centers, downregulated CD11c, underwent class switch recombination, and became switched memory cells. Yet other donor cells were maintained as IgM memory cells, and these IgM memory cells retained their multi-lineage potential following serial transfer. These findings were corroborated at the molecular level using immune repertoire analyses. Thus, IgM memory cells can differentiate into all effector B cell lineages and undergo self-renewal, properties that are characteristic of stem cells. We propose that these memory cells exist to provide long-term multi-functional immunity and act primarily to maintain the production of protective antibodies.

CD11c+ T-bet+ memory B cells: Immune maintenance during chronic infection and inflammation?

CD11c+ T-bet+ B cells have now been detected and characterized in different experimental and clinical settings, in both mice and humans. Whether such cells are monolithic, or define subsets of B cells with different functions is not yet known. Our studies have identified CD11c+ IgM+ CD19hi splenic IgM memory B cells that appear at approximately three weeks post-ehrlichial infection, and persist indefinitely, during low-level chronic infection. Although the CD11c+ T-bet+ B cells we have described are distinct, they appear to share many features with similar cells detected under diverse conditions, including viral infections, aging, and autoimmunity. We propose that CD11c+ T-bet+ B cells as a group share characteristics of memory B cells that are maintained under conditions of inflammation and/or low-level chronic antigen stimulation. In some cases, these cells may be advantageous, by providing immunity to re-infection, but in others may be deleterious, by contributing to aged-associated autoimmune responses.

Early derivation of IgM memory cells and bone marrow plasmablasts.

IgM memory cells are recognized as an important component of B cell memory in mice and humans. Our studies of B cells elicited in response to ehrlichial infection identified a population of CD11c-positive IgM memory cells, and an IgM bone marrow antibody-secreting cell population. The origin of these cells was unknown, although an early T-independent spleen CD11c- and T-bet-positive IgM plasmablast population precedes both, suggesting a linear relationship. A majority of the IgM memory cells detected after day 30 post-infection, also T-bet-positive, had undergone somatic hypermutation, indicating they expressed activation-induced cytidine deaminase (AID). Therefore, to identify early AID-expressing precursor B cells, we infected an AID-regulated tamoxifen-inducible Cre-recombinase-EYFP reporter strain. Tamoxifen administration led to the labeling of both 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, although IgM memory cells were marked when tamoxifen was administered as early as day 4 post-infection. Transcription of Aicda in the early plasmablasts was not detected in the absence of CD4 T cells, but occurred independently of TLR signaling. Unlike the IgM memory cells, the bone marrow IgM ASCs were elicited independent of T cell help. Moreover, Aicda was constitutively expressed in IgM memory cells, but not in bone marrow ASCs. These studies demonstrate that two distinct long-term IgM-positive B cell populations are generated early in response to infection, but are maintained via separate mechanisms.