Know Your ABCs: Discovery, Differentiation, and Targeting of T-Bet+ B Cells

Abstract

Since their first description in 2008, T-bet+ B cells have emerged as a clinically important B cell subset. Now commonly known as ABCs (Age-associated B Cells), they are uniquely characterized by their expression of the transcription factor T-bet. Indeed, this singular factor defines this B cell subset. This review will describe the discovery of T-bet+ B cells, their role in bacterial infection as T cell-independent (TI) plasmablasts, as well as long-term follicular helper T cell-dependent (TD) IgM+ and switched memory cells (i.e., T-bet+ ABCs), and later discoveries of their role(s) in diverse immunological responses. These studies highlight a critical, although limited, role of T-bet in IgG2a class switching, a function central to the cells' role in immunity and autoimmunity. Given their association with autoimmunity, pharmacological targeting is an attractive strategy for reducing or eliminating the B cells. T-bet+ ABCs express a number of characteristic cell surface markers, including CD11c, CD11b, CD73, and the adenosine 2a receptor (A2aR). Accordingly, A2aR agonist administration effectively targeted T-bet+ ABCs in vivo. Moreover, agonist treatment of lupus-prone mice reduced autoantibodies and disease symptoms. This latter work highlights the potential therapeutic use of adenosine agonists for treating autoimmune diseases involving T-bet+ ABCs.

Keywords: ABCs; CD11c; T‐bet B cells; adenosine receptor; age‐associated B cells; ehrlichia.

FIGURE 1

Heterogeneity of T‐bet + ABCs. A Venn diagram is shown that illustrates the populations of T‐bet+ memory ABCs detected in the spleens of E. muris‐infected mice. These include CD11c‐negative and ‐positive B cells; within these two major populations are cells that are switched and nonswitched (indicated with cross‐hatching), as well as cells that had expressed or lacked the enzyme AICDA (in green and orange). (Reproduced, with permission, from Kenderes et al. ref. [8]).

FIGURE 2

A model for the differentiation of T‐bet+ B cell‐derived plasmablasts and T‐bet+ ABCs in secondary lymphoid tissues during ehrlichial infection. The schematic describes the CD4 TI IgM+ T‐bet+ plasmablast response (1–2), and the generation and differentiation of TD memory T‐bet+ ABCs (3–6). Note that the two responses are temporally and anatomically distinct; the spleen T‐bet+ plasmablast response reaches a maxima on about day 18 postinfection and the T‐bet+ memory ABC response is fully developed at about 30 days postinfection. The latter response may occur primarily in the lymph nodes. The early spleen T‐bet+ plasmablast response (1) develops extrafollicularly, independent of GCs, and leads to the generation of short‐lived IgM+ T‐bet+ plasmablasts. Some of these T‐bet+ plasmablasts migrate to the bone marrow to become long‐lived IgM+ antibody‐secreting cells that provide long‐term immunity to ehrlichial infection (2). Later during the B cell response, CD4 T cell‐dependent T‐bet+ ABCs undergo differentiation, likely in B cell follicles (3). Help via IL‐21 and IFNγ is provided by Type I follicular helper T cells. Some of the T‐bet+ ABCs differentiate to CD11c + and −negative IgM memory cells, which undergo interconversion (4). Following reinfection or the introduction of antigen, the IgM+ T‐bet+ memory ABCs undergo clonal expansion and diversification, likely in GCs (5). The light and dark zones of the GCs are hatched to indicate that these structures may not be fully intact. This process leads to the generation of switched T‐bet+ memory ABCs, and some of these memory cells fully differentiate into IgG2a‐producing plasma cells.