Abstract
CTLA-4 is an important regulator of T-cell function. Here, we report that expression of this immune-regulator in mouse B-1a cells has a critical function in maintaining self-tolerance by regulating these early-developing B cells that express a repertoire enriched for auto-reactivity. Selective deletion of CTLA-4 from B cells results in mice that spontaneously develop autoantibodies, T follicular helper (Tfh) cells and germinal centers (GCs) in the spleen, and autoimmune pathology later in life. This impaired immune homeostasis results from B-1a cell dysfunction upon loss of CTLA-4. Therefore, CTLA-4-deficient B-1a cells up-regulate epigenetic and transcriptional activation programs and show increased self-replenishment. These activated cells further internalize surface IgM, differentiate into antigen-presenting cells and, when reconstituted in normal IgH-allotype congenic recipient mice, induce GCs and Tfh cells expressing a highly selected repertoire. These findings show that CTLA-4 regulation of B-1a cells is a crucial immune-regulatory mechanism.
Highlights
CTLA-4 is an important regulator of T-cell function
We further show that CD138+ plasma cells (PCs), which are derived from B-1a cells and secret IgM in resting mice[15], express Ctla[4] (Fig. 1a)
Using a monoclonal antibody that detects IgG1 of IgHa-haplotype mice but does not react with IgHb haplotype[49], we further show that these IgG1-expressing germinal centers (GCs) B cells express donor a-haplotype (IgG1a), indicating that they are derived from the transferred CTLA-4-deficient B-1a cells (IgHa), rather than the endogenous B cells from the CB.[17] recipients (IgHb) (Fig. 7d)
Summary
CTLA-4 is an important regulator of T-cell function. Here, we report that expression of this immune-regulator in mouse B-1a cells has a critical function in maintaining self-tolerance by regulating these early-developing B cells that express a repertoire enriched for autoreactivity. CTLA-4-deficient B-1a cells upregulate epigenetic and transcriptional activation programs and show increased selfreplenishment These activated cells further internalize surface IgM, differentiate into antigen-presenting cells and, when reconstituted in normal IgH-allotype congenic recipient mice, induce GCs and Tfh cells expressing a highly selected repertoire. These findings show that CTLA-4 regulation of B-1a cells is a crucial immune-regulatory mechanism. More recent studies have shown that B-1a cells are derived from the precursors around E8.5-E9.5 in the yolk sac and para-aortic splanchnopleura independent of the hematopoietic stem cells[9,10,11] In accordance with these developmental distinctions, our previous study has demonstrate that the B-1a IgH repertoire differs dramatically from the repertories expressed FOB and MZB cells[12]. The dependence on BCR signaling for B-1a generation is further evident in studies showing that mutations that disrupt BCR signaling result in the decrease or even elimination of B-1a cells, whereas deletion of the negative regulators of BCR signaling increases their numbers[1,2]
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