Uhrf1 regulates germinal center B cell expansion and affinity maturation to control viral infection

J Exp Med. 2018 May 7;215(5):1437-1448. doi: 10.1084/jem.20171815. Epub 2018 Apr 4.


The production of high-affinity antibody is essential for pathogen clearance. Antibody affinity is increased through germinal center (GC) affinity maturation, which relies on BCR somatic hypermutation (SHM) followed by antigen-based selection. GC B cell proliferation is essentially involved in these processes; it provides enough templates for SHM and also serves as a critical mechanism of positive selection. In this study, we show that expression of epigenetic regulator ubiquitin-like with PHD and RING finger domains 1 (Uhrf1) was markedly up-regulated by c-Myc-AP4 in GC B cells, and it was required for GC response. Uhrf1 regulates cell proliferation-associated genes including cdkn1a, slfn1, and slfn2 by DNA methylation, and its deficiency inhibited the GC B cell cycle at G1-S phase. Subsequently, GC B cell SHM and affinity maturation were impaired, and Uhrf1 GC B knockout mice were unable to control chronic virus infection. Collectively, our data suggest that Uhrf1 regulates GC B cell proliferation and affinity maturation, and its expression in GC B cells is required for virus clearance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Affinity*
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / metabolism*
  • Base Sequence
  • CCAAT-Enhancer-Binding Proteins
  • Cell Proliferation
  • Cell Survival
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA Methylation
  • Genetic Loci
  • Germinal Center / cytology*
  • Lymphocytic choriomeningitis virus / physiology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nuclear Proteins / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Somatic Hypermutation, Immunoglobulin
  • Ubiquitin-Protein Ligases
  • Up-Regulation
  • Virus Diseases / immunology*


  • CCAAT-Enhancer-Binding Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-myc
  • Ubiquitin-Protein Ligases
  • Uhrf1 protein, mouse