Gammaherpesvirus-mediated repression reveals EWSR1 to be a negative regulator of B cell responses

• Published in: Proceedings of the National Academy of Sciences - PNAS 2022-08, Vol.119 (32), p.e2123362119
• Main Authors: Wang, Yiping, Feswick, April, Apostolou, Vasiliki, Petkov, Petko M, Moser, Emily K, Tibbetts, Scott A
• Format: Article
• Language: English
• Subjects: Ablation; Animals; Antibodies; Antigens; Autoimmunity; B-Lymphocytes - immunology; B-Lymphocytes - virology; Biological Sciences; Cell proliferation; Clonal deletion; Deletion; Down-regulation; Epstein-Barr virus; Ewing's sarcoma; Ewings sarcoma; FLI-1 protein; Fusion protein; Gammaherpesvirinae - genetics; Gammaherpesvirinae - physiology; Gene Deletion; Germinal Center - immunology; Germinal Center - virology; Herpesviridae Infections - genetics; Herpesviridae Infections - immunology; Herpesviridae Infections - virology; Immune response; Immune system; Latency; Latent infection; Lymphocytes B; Mice; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Plasma cells; Ribonucleic acid; RNA; RNA-Binding Protein EWS - genetics; RNA-Binding Protein EWS - metabolism; Sarcoma; Splicing; Tumor Virus Infections - genetics; Tumor Virus Infections - immunology; Tumor Virus Infections - virology; Tumorigenesis; Virus Latency
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2123362119

The germinal center (GC) plays a central role in the generation of antigen-specific B cells and antibodies. Tight regulation of the GC is essential due to the inherent risks of tumorigenesis and autoimmunity posed by inappropriate GC B cell processes. Gammaherpesviruses such as Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68) utilize numerous armaments to drive infected naïve B cells, independent of antigen, through GC reactions to expand the latently infected B cell population and establish a stable latency reservoir. We previously demonstrated that the MHV68 microRNA (miRNA) represses host (Ewing sarcoma breakpoint region 1) to promote B cell infection. EWSR1 is a transcription and splicing regulator that is recognized for its involvement as a fusion protein in Ewing sarcoma. A function for EWSR1 in B cell responses has not been previously reported. Here, we demonstrate that 1) B cell-specific deletion of EWSR1 had no effect on generation of mature B cell subsets or basal immunoglobulin levels in naïve mice, 2) repression or ablation of EWSR1 in B cells promoted expansion of MHV68 latently infected GC B cells, and 3) B cell-specific deletion of EWSR1 during a normal immune response to nonviral antigen resulted in significantly elevated numbers of antigen-specific GC B cells, plasma cells, and circulating antibodies. Notably, EWSR1 deficiency did not affect the proliferation or survival of GC B cells but instead resulted in the generation of increased numbers of precursor GC B cells. Cumulatively, these findings demonstrate that EWSR1 is a negative regulator of B cell responses.