Atypical is the new norm, for B cells and the rest of us

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Science Immunology  02 Apr 2021:
Vol. 6, Issue 58, eabi7304
DOI: 10.1126/sciimmunol.abi7304


An unusual form of activated B cells in adults is described, called atypical B cells, both in the steady state and after vaccination.

Most immunology textbooks divide B cells into two camps: follicular (e.g., B2) and innate-like B cells (e.g., marginal zone, B1), which respond to different types of stimuli and play different roles in the immune response. Activated follicular B cells are assumed to primarily participate in germinal center (GC) reactions to produce highly specific antibodies. However, not all B cell responses fit neatly into this paradigm. Subsets of B cells identified in the context of infection, aging, cancer, and autoimmunity display unusual cell surface markers in mice and humans but, possibly due to differing nomenclature used over the years, have remained enigmatic. These “atypical” B cells have been variably called inflammatory, extrafollicular, double negative (DN), or age-associated (ABCs) B cells and depending on the study, express CD11c, Tbet, FcRL4 but lack CD21, CD27 and IgD. The exact relationship between these populations remains unclear, but they are often described as chronically activated, pro-inflammatory B cells.

Using single cell RNA sequencing and Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq) of blood B cells, Sutton et al. now demonstrate that atypical B cells are also present and common in healthy adults. They started by characterizing antigen-specific B cells in individuals immunized against or infected with malaria and identified a cell population consistent with atypical B cells. However, Sutton and colleagues also noted the presence of atypical B cells in unexposed healthy controls via transcriptional analyses. They were able to reconcile this finding with previous work by demonstrating that B cells with an atypical transcriptional profile had heterogeneous expression of “classic” cell surface markers by antibody staining. Using influenza vaccine challenge and sporozoite immunization, the authors show that expression of cell surface markers differed based on the stage of atypical B cell activation. More work is needed to establish the breadth and dynamics of atypical B cells, especially in healthy individuals, and a central unresolved issue is whether this alternative B cell activation fate results in qualitatively different antibodies from the more traditional GC-derived pathway. One thing however is clear: These atypical B cells may be more typical than previously appreciated.

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