Long-primed germinal centres with enduring affinity maturation and clonal migration

Nature. 2022 Sep;609(7929):998-1004. doi: 10.1038/s41586-022-05216-9. Epub 2022 Sep 21.

Abstract

Germinal centres are the engines of antibody evolution. Here, using human immunodeficiency virus (HIV) Env protein immunogen priming in rhesus monkeys followed by a long period without further immunization, we demonstrate germinal centre B (BGC) cells that last for at least 6 months. A 186-fold increase in BGC cells was present by week 10 compared with conventional immunization. Single-cell transcriptional profiling showed that both light- and dark-zone germinal centre states were sustained. Antibody somatic hypermutation of BGC cells continued to accumulate throughout the 29-week priming period, with evidence of selective pressure. Env-binding BGC cells were still 49-fold above baseline at 29 weeks, which suggests that they could remain active for even longer periods of time. High titres of HIV-neutralizing antibodies were generated after a single booster immunization. Fully glycosylated HIV trimer protein is a complex antigen, posing considerable immunodominance challenges for B cells1,2. Memory B cells generated under these long priming conditions had higher levels of antibody somatic hypermutation, and both memory B cells and antibodies were more likely to recognize non-immunodominant epitopes. Numerous BGC cell lineage phylogenies spanning more than the 6-month germinal centre period were identified, demonstrating continuous germinal centre activity and selection for at least 191 days with no further antigen exposure. A long-prime, slow-delivery (12 days) immunization approach holds promise for difficult vaccine targets and suggests that patience can have great value for tuning of germinal centres to maximize antibody responses.

MeSH terms

  • Animals
  • Antibodies, Neutralizing / genetics
  • Antibodies, Neutralizing / immunology
  • Antibody Affinity* / genetics
  • Antibody Affinity* / immunology
  • B-Lymphocytes* / cytology
  • B-Lymphocytes* / immunology
  • Cell Movement*
  • Clone Cells* / cytology
  • Clone Cells* / immunology
  • Epitopes, B-Lymphocyte / immunology
  • Gene Expression Profiling
  • Germinal Center* / cytology
  • Germinal Center* / immunology
  • HIV Antibodies* / genetics
  • HIV Antibodies* / immunology
  • HIV Infections / immunology
  • HIV-1 / immunology
  • Humans
  • Immunization*
  • Immunization, Secondary
  • Macaca mulatta / immunology
  • Macaca mulatta / virology
  • Memory B Cells / cytology
  • Memory B Cells / immunology
  • Single-Cell Analysis
  • Somatic Hypermutation, Immunoglobulin / genetics
  • Somatic Hypermutation, Immunoglobulin / immunology
  • Time Factors
  • env Gene Products, Human Immunodeficiency Virus / administration & dosage
  • env Gene Products, Human Immunodeficiency Virus / immunology

Substances

  • Antibodies, Neutralizing
  • Epitopes, B-Lymphocyte
  • HIV Antibodies
  • env Gene Products, Human Immunodeficiency Virus