Stem cell-like T-bet+ IgM memory cells generate multi-lineage effector B cells

Abstract

Abstract Our laboratory has been studying the differentiation of CD11c+ T-bet+ IgM memory B cells during secondary ehrlichial infection. These cells are closely related to B cells that have been described in a range of other contexts, including hepatitis, AIDs, malaria, SLE, and age-related autoimmunity. Following secondary infection, IgM memory cells, as a population, undergo self-renewal, and differentiate into effector cells, including splenic and bone marrow antibody secreting cells (ASC). Moreover, IgM memory cells enter germinal centers, where they undergo class-switch recombination and give rise to class-switched memory and effector cells. Although these data suggest that a single memory cell has multi-lineage potential, we sought to formally address this question by searching for shared clones among IgM memory cell-derived effector cells. Among the IgM memory cell-derived subsets, we identified several clones common to all effector cell populations. The number of common clones varied for each pairwise comparison of effector cells and suggested lineal relationships. IgM memory cells accumulated mutations following rechallenge; although all memory cell-derived subsets displayed similar numbers of V region mutations. Lineage analysis demonstrated that the effector cell subsets underwent varying degrees of clonal diversification, although this was clone-dependent. These studies reveal that a single IgM memory cell clone can give rise to different memory and effector cell subsets, that is, they exhibit stem cell properties. This property distinguishes these T-bet+ IgM memory cells as a unique memory cell subset.