The majority of circulating human B cells belong to a na?ve anergic B cell subset distinguished by expression of CD73

Abstract In humans, it is estimated that ~40% of peripheral blood (PB) naïve (CD19 +CD27 −CD45RB MEM−CD38 −) B cells are in a state of anergy defined as IgD +IgM low. Presumably these anergic B cells express only weakly autoreactive B cell receptors (BCR) that allowed them to escape elimination by central tolerance mechanisms in the bone marrow, but were sufficient to induce anergy in the periphery. Although the ultimate fate of these B cells is not known, it is hypothesized that anergic B cells undergo a process of redemption in which they are activated and somatically hypermutate away from self, allowing them to be recruited into foreign antigen-specific responses. To better characterize human anergic B cells, we utilized a panel of 18 antibodies specific for B cell surface markers and BCR isotypes, which allowed identification of the known human B cell subsets by flow cytometry. We determined that ~50% of B cells were contained in the naïve compartment, of which ~60% were anergic (IgD +IgM low) cells distinguished by the expression of CD73. In contrast, CD11c +CD27 −B cells (termed ABCs) and CD45RB +CD27 −MBCs comprised only 0.6% and 7.0% of circulating anergic B cells, respectively. Using 9G4 to identify inherently autoreactive B cells expressing germline VH4–34, we found that the majority of 9G4 +cells were naïve anergic B cells that express CD73. Thus, in humans the CD73 +naïve compartment appears to be the major reservoir of anergic B cells, possibly for redemption and participation in immune responses to pathogens. Studies are underway to define the responses of these B cells in health and disease. This work was supported by the Intramural Research Program of the US National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Institute of Arthritis and Musculoskeletal and Skin Diseases.