IRF5 Loss Impairs TLR9/BCR-Induced B Cell Activation, Proliferation and Plasmablast Differentiation through Erk1-Myc Signaling

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 seen in autoimmune diseases, such as sytemic lupus erythematosus (SLE), and certain B cell-associated malignancies. Studies suggest that altered expression of regulatory transcription factors play a role in the observed imbalance of B cell subsets in these diseases. The transcription factor interferon regulatory factor 5 (IRF5) is one such candidate as polymorphisms in IRF5 associate with risk of numerous autoimmune diseases and correlate with elevated IRF5 expression. Furthermore, dysregulated IRF5 expression and activation have been implicated in a variety of B cell lymphoproliferative disorders. It remains unclear, however, whether IRF5 has a role in normal B cell function. To date, little is known of IRF5 function in human B cells. We utilized human primary naïve B cells combined with IRF5 knockdown to identify a critical new intrinsic role for IRF5 in B cell activation, proliferation and plasma cell differentiation. IRF5 knockdown resulted in significant IgD 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, IRF4, ERK1, and MYC, and signaling 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 disease. DisclosuresNo relevant conflicts of interest to declare.