Abstract
Regulated apoptosis of germinal centre (GC) B cells is critical for normal humoral immune responses. ELL-associated factor 2 (EAF2) regulates transcription elongation and has been shown to be an androgen-responsive potential tumour suppressor in prostate by inducing apoptosis. Here we show that EAF2 is selectively upregulated in GC B cells among various immune cell types and promotes apoptosis of GC B cells both in vitro and in vivo. EAF2 deficiency results in enlarged GCs and elevated antibody production during a T-dependent immune response. After immunization with type II collagen, mice lacking EAF2 produce high levels of collagen-specific autoantibodies and rapidly develop severe arthritis. Moreover, the mutant mice spontaneously produce anti-dsDNA, rheumatoid factor and anti-nuclear antibodies as they age. These results demonstrate that EAF2-mediated apoptosis in GC B cells limits excessive humoral immune responses and is important for maintaining self-tolerance.
Highlights
Regulated apoptosis of germinal centre (GC) B cells is critical for normal humoral immune responses
Eaf[2] is an apoptosis inducer highly expressed by GC B cells
A comparison of gene expression profiles among various immune cell subpopulation identified Eaf[2], a gene implicated in the apoptosis of prostate cancer cells[21], as selectively upregulated in the GC B cells but not in naive B or B cells activated in vitro by the various stimuli (Supplementary Fig. 1a), or in spleen T cells a 24 h green fluorescent protein (GFP)
Summary
Regulated apoptosis of germinal centre (GC) B cells is critical for normal humoral immune responses. ELL-associated factor 2 (EAF2) regulates transcription elongation and has been shown to be an androgen-responsive potential tumour suppressor in prostate by inducing apoptosis. The mutant mice spontaneously produce anti-dsDNA, rheumatoid factor and anti-nuclear antibodies as they age These results demonstrate that EAF2-mediated apoptosis in GC B cells limits excessive humoral immune responses and is important for maintaining self-tolerance. EAF2 deficiency causes enlarged GC and elevated humoral immune responses and high susceptibility to collagen-induced arthritis (CIA) and autoantibody production. These findings identify EAF2 as a GC B-specific apoptosis inducer in the immune system that functions to maintain the balance between immunity and tolerance
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