Generation of functional murine CD11c⁺ age‐associated B cells in the absence of B cell T‐bet expression

Abstract

Age-associated B cells (ABC), a novel subset of activated B cells defined by CD11b and CD11c expression, have been linked with both protective anti-viral responses and the pathogenesis of systemic autoimmunity. Expression of the TH1 lineage transcription factor T-bet has been identified as a defining feature of ABC biology, with B cell-intrinsic expression of this transcription factor proposed to be required for ABC formation. In contrast to this model, we report that Tbx21 (encoding T-bet)-deficient B cells upregulate CD11b and CD11c surface expression in vitro in response to integrated TLR and cytokine signals. Moreover, B cell-intrinsic T-bet deletion in a murine lupus model exerted no impact of ABC generation in vivo, with Tbx21−/− ABCs exhibiting an identical surface phenotype to wild-type (WT) ABCs. Importantly, WT and Tbx21−/− ABCs sorted from autoimmune mice produced equivalent amounts of IgM and IgG ex vivo following TLR stimulation, indicating that T-bet-deficient ABCs are likely functional in vivo. In summary, our data contradict the established literature by demonstrating that T-bet expression is not uniformly required for ABC generation.

The IL‐12‐STAT4 axis in the pathogenesis of human systemic lupus erythematosus

“…The accessible chromatin of CD11c + DN B cells in human SLE was specifically enriched for T-bet motifs [14], suggesting that T-bet is actively modifying transcripts in human CD11c + DN B cells and contributes to their generation and/or function. Consistently, conditional deletion of T-bet in B cells was sufficient in several lupus mouse models (but not in all for example WAS −/− B cell model [21]) to decrease the generation of ABCs, GC activity, nephritis, and mortality [17], suggesting that the transcriptional activity of T-bet in B cells is also critical in murine lupus.…”

CD11c+ B Cells Are Mainly Memory Cells, Precursors of Antibody Secreting Cells in Healthy Donors

“…However, not all CD11c + B cells are T-bet + in SLE patients or HD, and some Tbet + B cells do not express CD11c (12). Moreover, B-cell-intrinsic T-bet deletion in a murine lupus model exerted no impact of CD11c + B cells generation in vivo (16).…”

“…However, CD11c + B cells are detected in young healthy donors (HD) as well (14). This broad range of conditions could reflect their state of activation depending on the disease or age and might explain why cell surface expression of CD11c + B cells has been reported to be heterogeneous, corresponding to: CD27 + memory cell (9), double-negative (DN) IgD − CD27 − (13), CD21 low (10), and T-bet + (12,15) or T-bet − , at least in mice (16). In addition, we reported previously that following tolllike receptor 9 (TLR9) and B-cell receptor (BCR) stimulation, CD11c + B cells from HD were unable to secrete interleukin (IL)- 10 (14), while IL-10 is one of the highest messenger RNA (mRNA) expressed found in CD11c + B cells from SLE patient (12).…”

IFNγ induces epigenetic programming of human T-bethi B cells and promotes TLR7/8 and IL-21 induced differentiation

“…For example, two IFNγ-inducible proteins, CXCR3 and T-bet, are more highly expressed by circulating B cells from SLE patients compared to healthy controls (Harigai et al, 2008; Nicholas et al, 2008; Lit et al, 2007; Wang et al, 2018; Jenks et al, 2018). Moreover, data from mouse SLE models show that clinical disease is dependent on B cell-specific expression of the IFNγR and the IFNγ- induced transcription factors (TF) STAT1 (Domeier et al, 2016; Jackson et al, 2016; Thibault et al, 2008) and T-bet in some (Rubtsova et al, 2017; Liu et al, 2017) but not all (Jackson et al, 2016; Du et al, 2019) models. Taken together, these data suggest that IFNγ-driven inflammation may contribute to SLE B cell-driven pathophysiology.…”