2. Academic Validation
  3. Affinity-Restricted Memory B Cells Dominate Recall Responses to Heterologous Flaviviruses

Affinity-Restricted Memory B Cells Dominate Recall Responses to Heterologous Flaviviruses

  • Immunity. 2020 Nov 17;53(5):1078-1094.e7. doi: 10.1016/j.immuni.2020.09.001.
Rachel Wong 1,  Julia A Belk 2,  Jennifer Govero 3,  Jennifer L Uhrlaub 4,  Dakota Reinartz 4,  Haiyan Zhao 5,  John M Errico 5,  Lucas D'Souza 4,  Tyler J Ripperger 4,  Janko Nikolich-Zugich 4,  Mark J Shlomchik 6,  Ansuman T Satpathy 2,  Daved H Fremont 5,  Michael S Diamond 7,  Deepta Bhattacharya 8
Affiliations

Affiliations

  • 1 Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Immunobiology, University of Arizona, Tucson, AZ 85724, USA.
  • 2 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 3 Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
  • 4 Department of Immunobiology, University of Arizona, Tucson, AZ 85724, USA.
  • 5 Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
  • 6 Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
  • 7 Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
  • 8 Department of Immunobiology, University of Arizona, Tucson, AZ 85724, USA. Electronic address: deeptab@arizona.edu.
PMID: 33010224 DOI: 10.1016/j.immuni.2020.09.001
Abstract

Memory B cells (MBCs) can respond to heterologous antigens either by molding new specificities through secondary germinal centers (GCs) or by selecting preexisting clones without further affinity maturation. To distinguish these mechanisms in Flavivirus infections and immunizations, we studied recall responses to envelope protein domain III (DIII). Conditional deletion of activation-induced cytidine deaminase (AID) between heterologous challenges of West Nile, Japanese encephalitis, Zika, and dengue viruses did not affect recall responses. DIII-specific MBCs were contained mostly within the plasma-cell-biased CD80+ subset, and few GCs arose following heterologous boosters, demonstrating that recall responses are confined by preexisting clonal diversity. Measurement of monoclonal antibody (mAb) binding affinity to DIII proteins, timed AID deletion, single-cell RNA Sequencing, and lineage tracing experiments point to selection of relatively low-affinity MBCs as a mechanism to promote diversity. Engineering immunogens to avoid this MBC diversity may facilitate flavivirus-type-specific vaccines with minimized potential for Infection enhancement.

Keywords

Dengue virus; Japanese Encephalitis virus; West Nile virus; Zika virus; flaviruses; germinal center; memory B cells; plasma cells.

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