IRF4 and IRF5 transcription factors exhibit shared and distinct roles in regulating human B cell differentiation and function

Abstract

Abstract Upon recognition of antigen, B cells undergo rapid proliferation followed by differentiation to specialized antibody secreting cells (ASCs). Increased levels of ASCs are seen in autoimmune diseases, such as systemic lupus erythematosus (SLE), and some B cell-associated malignancies. Studies suggest that altered transcription factor (TF) expression and/or activation play a role in the imbalance of B cell subsets in these diseases. Interferon regulatory factor 5 (IRF5) is one such TF, as polymorphisms in IRF5 associate with risk of numerous autoimmune diseases and correlate with elevated IRF5 expression in SLE patients. Recent findings from IRF5 knockdown (KD) in purified naïve B cells identified IRF5 as an early intrinsic regulator of B cell activation, proliferation and plasma cell differentiation in response to TLR9 activation. In this study, IRF4 was identified as a new IRF5 target gene by ChIP-Seq and RNA-Seq analysis. IRF4 expression is high in ASCs and murine studies show that it plays an essential, cell-intrinsic role in the generation of germinal center B cells. To date, little is known of IRF4 function in human ASC differentiation or whether these two factors (IRF4 and 5) cooperate. Activation of TLR9 and B cell receptor (BCR) revealed distinct kinetic changes in IRF4 and IRF5 during the early transition of naïve B cells to ASCs. Moreover, IRF4 KD of human primary naïve B cells resulted in significant IgD retention and reduced plasmablast (PB) differentiation without loss of early B cell activation (CD86) or key regulatory factors of class switch recombination in response to TLR9/BCR stimulation. Together, these results show that IRF4 and IRF5 are kinetically distinct TFs that have non-redundant roles in human ASC differentiation.