An Integrated Multi-omic Single-Cell Atlas of Human B Cell Identity

Abstract

Summary B cells are capable of a wide range of effector functions including antibody secretion, antigen presentation, cytokine production, and generation of immunological memory. A consistent strategy for classifying human B cells by using surface molecules is essential to harness this functional diversity for clinical translation. We developed a highly multiplexed screen to quantify the co-expression of 351 surface molecules on millions of human B cells. We identified differentially expressed molecules and aligned their variance with isotype usage, VDJ sequence, metabolic profile, biosynthesis activity, and signaling response. Based on these analyses, we propose a classification scheme to segregate B cells from four lymphoid tissues into twelve unique subsets, including a CD45RB + CD27 − early memory population, a class-switched CD39 + tonsil-resident population, and a CD19 hi CD11c + memory population that potently responds to immune activation. This classification framework and underlying datasets provide a resource for further investigations of human B cell identity and function.

A dichotomy of gene regulatory associations during the activated B-cell to plasmablast transition

“…This conclusion is further supported by the similarities observed in ABC-DLBCL cell line data. Our understanding of heterogeneity in human peripheral blood B-cell populations is rapidly increasing (66). It will be interesting in future to address whether particular B-cell subsets show selective differences in gene regulation and key TF occupancy during the ABC to plasmablast transition.…”

Intrarenal B cells integratein situinnate and adaptive immunity in human renal allograft rejection

“…Herein, we demonstrate that in allograft rejection, intrarenal B cells have a unique gene expression profile that most closely resembles the B1 innate B cells that have been described in mice but not in humans (Baumgarth, 2017;Glass et al, 2020). In contrast to murine innate B cell populations, which are constitutively present (Baumgarth, 2017), Bin cells were associated with inflammation and overall transcriptional differences were most prominent in those cells expressing mutated IgG antibodies.…”

“…Indeed, one of the major differences between B cell populations in humans compared to mice is the lack of cells with an innate B1 cell transcriptional signature. While innate-like functions have been ascribed to human B cell subpopulations (Rothstein and Quach, 2015), extensive scRNA-seq has failed to confirm their existence (Glass et al, 2020). It was difficult to map Bin cells to known populations of human B cells.…”

Characterization and Phase 1 Trial of a B Cell Activating Anti-CD73 Antibody for the Immunotherapy of COVID-19

“…[11] Human CD73 is expressed on IgD POS IgM DIM/NEG naïve B cells, and CD27 POS memory B cells expressing IgG or IgA. [14] CPI-006 induces the expression of CD69, an activation marker that negatively regulates S1PR1 function, resulting in the prolonged retention of activated B cells in lymphoid organs and thymus. [27] This increased lymphoid residence time provides time to complete B cell activation and interact with CD4 POS T follicular helper cells to shape downstream immune responses.…”

“…[11,12] CD73 is expressed on subsets of human CD4 POS and CD8 POS T cells, germinal center follicular dendritic cells, and both naïve and class switched memory B cells. [12][13][14] A role for CD73 in B cell maturation has been proposed as reduced CD73 expression on B cells from patients with common variable immunodeficiency (CVID) correlates with an inability to produce IgG. [15,16] Like many glycosyl phosphatidylinositol (GPI)-anchored molecules, CD73 has been shown to transmit activation signals when ligated by antibodies, although a physiologic ligand for CD73 has not been identified.…”