B Cell-Intrinsic Role for IRF5 in TLR9/BCR-Induced Human B Cell Activation, Proliferation, and Plasmablast Differentiation

Abstract

Upon recognition of antigen, B cells undergo rapid proliferation followed by differentiation to specialized antibody secreting cells (ASCs). During this transition, B cells are reliant upon a multilayer transcription factor network to achieve a dramatic remodeling of the B cell transcriptional landscape. Increased levels of ASCs are often seen in autoimmune diseases and it is believed that altered expression of regulatory transcription factors play a role in this imbalance. The transcription factor interferon regulatory factor 5 (IRF5) is one such candidate as polymorphisms in <i>IRF5</i> associate with risk of numerous autoimmune diseases and correlate with elevated <i>IRF5</i> expression. <i>IRF5</i> genetic risk has been widely replicated in systemic lupus erythematosus (SLE), and loss of <i>Irf5</i> ameliorates disease in murine lupus models, in part, through the lack of pathogenic autoantibody secretion. It remains unclear, however, whether IRF5 is contributing to autoantibody production through a B cell-intrinsic function. To date, IRF5 function in healthy human B cells has not been characterized. Using human primary naive B cells, we define a critical intrinsic role for IRF5 in B cell activation, proliferation, and plasmablast differentiation. Targeted IRF5 knockdown resulted in significant immunoglobulin (Ig) D retention, reduced proliferation, plasmablast differentiation, and IgG secretion. The observed decreases were due to impaired B cell activation and clonal expansion. Distinct from murine studies, we identify and confirm new IRF5 target genes, <i>IRF4, ERK1</i>, and <i>MYC</i>, and pathways that mediate IRF5 B cell-intrinsic function. Together, these results identify IRF5 as an early regulator of human B cell activation and provide the first dataset in human primary B cells to map IRF5 dysfunction in SLE.