Precursor Frequency and Affinity Determine B Cell Competitive Fitness in Germinal Centers, Tested with Germline-Targeting HIV Vaccine Immunogens
By Robert K. Abbott, J. Lee, Sergey Menis, Patrick D. Skog, M. Rossi, T. Ota, Daniel W. Kulp, Deepika Bhullar, Oleksandr Kalyuzhniy, C. Havenar-Daughton and 3 more. 2017
313 citations recorded by the source corpus.
Summary How precursor frequencies and antigen affinities impact interclonal B cell competition is a particularly relevant issue for candidate germline‐targeting HIV vaccine designs because of the in vivo rarity of naive B cells that recognize broadly neutralizing epitopes. Knowing the frequencies and affinities of HIV‐specific VRC01‐class naive human B cells, we transferred B cells with germline VRC01 B cell receptors into congenic recipients to elucidate the roles of precursor frequency, antigen affinity, and avidity on B cell responses following immunization. All three factors were interdependently limiting for competitive success of VRC01‐class B cells. In physiological high‐affinity conditions using a multivalent immunogen, rare VRC01‐class B cells successfully competed in germinal centers (GC), underwent extensive somatic hypermutation, and differentiated into memory B cells. The data reveal dominant influences of precursor frequency, affinity, and avidity for interclonal GC competition and indicate that germline‐targeting immunogens can overcome these challenges with high‐affinity multimeric designs. Graphical Abstract Figure. No Caption available. HighlightsPrecursor frequency and affinity limit VRC01‐class B cell fitness upon immunizationFrequency and affinity constraints can be modulated by immunogen multivalencyPhysiologically rare VRC01‐class precursor B cells can successfully compete in GCsInterclonal competition in germinal centers can resolve within 2–3 weeks &NA; It is not clear how precursor frequencies and antigen affinities impact interclonal B cell competition. Abbott et al. show these parameters interdependently limit germinal center B cell fitness. When these variables are matched to the human physiological range, HIV bnAb precursor B cells compete in germinal centers, undergo extensive mutation, and form memory.
Subfields: Immunology, Virology
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Citations in the corpus
- Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus (2019, background): “…scaffolds to present complex glycoprotein antigens derived from influenza hemagglutinin (Kanekiyo et al., 2013;Yassine et al., 2015), HIV envelope (Abbott et al., 2018; He et al., 2016; Jardine et al., 2015; McGuire et al., 2016; Sliepen et al., 2015), and Epstein-Barr virus (Kanekiyo et al.,…”
- Glycan-Masking Focuses Immune Responses to the HIV-1 CD4-Binding Site and Enhances Elicitation of VRC01-Class Precursor Antibodies (2018, unknown): “A recent study has shown that antibody precursor affinity toward its cognate immunogen can have a large effect on B cell recruitment, differentiation, and antibody maturation (Abbott et al., 2018).”
- Design of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages (2018, unknown): “267 Newly recombined, naïve B cell receptors (BCRs) need to first recognize an immunogen 268 to initiate affinity maturation and B cell proliferation (41).”
- T follicular helper cell biology: A decade of discovery and diseases (2019, background): “The success of B cells competing for early Tfh help depends on the frequency of the B cells and their antigen affinity (Abbott et al., 2018; Schwickert et al., 2011).”