Table 1 Defining B-1 cells

In the early 1980s, it was observed that some cancerous B cells from patients with chronic lymphocytic leukemia expressed the T-cell marker CD5 (formerly known as Ly-1), which was later also found in mouse B cell lymphomas [3]. These findings instigated the search for non-cancerous B cells expressing CD5, which were found in low frequency in the spleen but in high frequency within the peritoneal and pleural cavities of healthy mice [4]. Murine B-1 cells are now phenotypically characterized by their surface markers IgM^high IgD^low CD19^high B220^low CD23⁻ CD43⁺ with CD5 distinguishing between B-1a (CD5⁺) and B-1b (CD5⁻), while the follicular B-2 cell is characterized by CD19⁺ B220⁺ CD23⁺ and CD43⁻. B-1 cells also express the integrin CD11b when inside serous cavities, but this marker is lost upon their migration to lymphatic vessels or spleen [5]. Besides the difference in CD5 expression, it was proposed that there is a division of labor between B-1a and B-1b cells [6], although this is still controversial. Additionally, it was recently shown that B-1a cells down-regulate CD5 expression after Toll-like receptor (TLR) stimulation [7], suggesting that B-1b cells might be only the activated form of B-1a cell. Although these surface markers constitute an easy way to differentiate B-1 from B-2 cells, many of these markers either do not encompass all B-1 cells or they can sometimes also be expressed by B-2 cells. Currently, the best way to distinguish B-1 cells and their antibodies from B-2 cells is the neonatal chimera model, in which host B-1 cells are replaced in neonatal mice by a congenic Ig-allotype-disparate donor B-1 cells while the B-2 cells remain of the host [8]

Whereas murine B-1 cells are well-characterized, the phenotypic markers for human B-1 cells are still not fully established. It has been proposed that circulating B-1 cells in humans are characterized by the surface markers CD19⁺ CD20⁺ CD27⁺ CD38^low/int CD43⁺. Further analysis demonstrated that 75% of cells bearing this phenotype express CD5 and share homologous functions with their murine counterpart, such as spontaneous antibody secretion [9]. Considering that CD43 can also be expressed by activated B-2 cells, the authors confirmed that these cells did not express other characteristic markers for B-2 cell activation such as CD69 and CD70 [9]. Thus, some characteristics that are ascribed to human memory B cells (identified by CD27 expression) are actually specific of B-1 cells [9]. Using spatial transcriptomics, a more extensive characterization of human B-1 cell was provided by identifying prenatal B-1 cells expressing CD5, CD27 and CD43 [10]. The authors also identified a subset of B-1 cells that express high levels of CCR10. These CCR10⁺ B-1 cells are highly proliferative and have shorter N-additions in the complementarity-determining region (CDR)3 junction in both immunoglobulin (Ig) heavy and light chains. They also confirmed that B-1 cells have the capacity to spontaneously secrete antibodies. The proportion of B-1 cells decrease from the first to the second trimester of gestation in almost every organ, except for the thymus, where the population of B-1 cells persisted [10]. Human B-1 cells and its ontogeny was recently reviewed by Kageyama et. al., [11]