B Cell Competition for Restricted T Cell Help Suppresses Rare-Epitope Responses

• Type of Material: Article
• Authors: Matthew Charles Woodruff, Emory University; Eui Ho Kim, Emory University; Wei Luo, Stanford University; Bali Pulendran, Emory University
• Language: English
• Date: 2018-10-09
• Publisher: Elsevier (Cell Press): OAJ
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s)
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2018.09.029
• Title of Journal or Parent Work: Cell Reports
• ISSN: 2211-1247
• Volume: 25
• Issue: 2
• Start Page: 321
• End Page: +
• Grant/Funding Information: We acknowledge funding from the NIH (R37 DK057665, R37 AI048638, U19 AI090023, T32 DK07656, and U19 AI057266 to B.P.), the Bill and Melinda Gates Foundation, and Action Cycling Atlanta (to M.C.W.) for supporting this work through grants and fellowships.
• Keywords: Life Sciences & Biomedicine; MEMORY; Science & Technology; VACCINES; CLONAL SELECTION; GERMINAL-CENTERS; INNATE IMMUNITY; Cell Biology; AFFINITY MATURATION
• Research Categories: Biology, Cell

Abstract

The immune system responds preferentially to particular antigenic-epitopes contained within complex immunogens, such as proteins or microbes. This poorly understood phenomenon, termed “immunodominance,” remains an obstacle to achieving polyvalent immune responses against multiple antigenic-epitopes through vaccination. We observed profound suppression in the hapten-specific antibody response in mice immunized with hapten-protein conjugate, mixed with an excess of protein, relative to that in mice immunized with hapten-protein alone. The suppression was robust (100-fold and 10-fold with a 10- or 2-fold excess of protein, respectively), stable over a 6-log range in antigen dose, observed within 10 days of vaccination, and resistant to boosting and adjuvants. Furthermore, there were reduced frequencies of antigen-specific germinal-center B cells and long-lived bone-marrow plasma cells. The mechanism of this “antigen-competition” was mediated largely by early access to T-helper cells. These results offer mechanistic insights into B cell competition during an immune response and suggest vaccination strategies against HIV, influenza, and dengue. Vaccination success depends on the immune system's ability to produce antibodies against highly specific pathogen targets, but the rules for how targets are selected remains poorly understood. Woodruff et al. describe a competition for resources among antibody producers that selects the cells, and thus targets, of the ensuing response.