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Comparative Study
. 2019 Mar 8;10(1):1126.
doi: 10.1038/s41467-019-09085-1.

Systematic comparison of respiratory syncytial virus-induced memory B cell responses in two anatomical compartments

Laila Shehata  1 , Wendy F Wieland-Alter  2 , Daniel P Maurer  1 , Eunice Chen  3 , Ruth I Connor  2 , Peter F Wright  2 , Laura M Walker  4
Affiliations
Comparative Study

Systematic comparison of respiratory syncytial virus-induced memory B cell responses in two anatomical compartments

Laila Shehata et al. Nat Commun. .

Abstract

Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants and young children. Although it is widely agreed that an RSV vaccine should induce both mucosal and systemic antibody responses, little is known about the B cell response to RSV in mucosa-associated lymphoid tissues. Here, we analyze this response by isolating 806 RSV F-specific antibodies from paired adenoid and peripheral blood samples from 4 young children. Overall, the adenoid-derived antibodies show higher binding affinities and neutralization potencies compared to antibodies isolated from peripheral blood. Approximately 25% of the neutralizing antibodies isolated from adenoids originate from a unique population of IgM+ and/or IgD+ memory B cells that contain a high load of somatic mutations but lack expression of classical memory B cell markers. Altogether, the results provide insight into the local B cell response to RSV and have implications for the development of vaccines that stimulate potent mucosal responses.

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Conflict of interest statement

L.M.W., L.S. and D.P.M. are shareholders in Adimab, LLC. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1
RSV F-specific B cell responses in the adenoids and peripheral blood of young children. Shown is the frequency of RSV F-specific B cells among CD19+ B cells in adenoid (left) and PBMCs (right) for a representative donor (a) and a summary for all 6 donors analyzed (b). The frequency of RSV F-reactive B cells within the CD14—CD3—CD8—CD19+ population is shown inside the gate. Asterisks in b indicate B cell responses that were below the limit of detection. c Index sort analysis of surface markers expressed on B cells from which RSV F-reactive antibodies were isolated. d Isotype distribution of RSV F-specific B cells in adenoid and PBMCs. e Percentage of RSV F-reactive, FcRL4+ B cells within each memory B cell subset described in c
Fig. 2
Fig. 2
Sequence characteristics of RSV F-specific antibodies. a Median number of VH nucleotide substitutions in RSV F-specific antibodies isolated from adenoids or PBMCs. b Number of VH nucleotide substitutions in antibodies isolated from each B cell subset. Each point represents an individual antibody. Black bars indicate median values. c Percentage of RSV F-specific atypical memory B cells (defined as CD19+IgG—IgA—CD27— and containing SHM) in adenoids and peripheral blood. d Percentage of RSV F-specific CD19+CD27— B cells in the adenoids of each donor that are class-switched or express IgM and/or IgD. e Percentage of CD19+RSV-F+CD27—IgM+/IgD+ adenoid B cells expressing CD5 or CD45RBMEM55. Statistical comparisons were made using the Mann-Whitney test and Fisher’s exact test (****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05, n.s. not significant). Nt, nucleotide; swIg, switched Ig
Fig. 3
Fig. 3
Binding properties of RSV F-specific antibodies isolated from adenoids and PBMCs. a Percentage of antibodies isolated from adenoids or PBMCs that are preF-specific, preF/postF-cross-reactive, or postF-specific (n = 808 antibodies). b Percentage of antibodies isolated from adenoids or PBMCs with the indicated apparent affinities for preF (n = 808 antibodies). N.B. non-binding. Results are representative of two independent experiments
Fig. 4
Fig. 4
Neutralizing activity of RSV F-specific antibodies isolated from adenoids and PBMCs. a Percentage of antibodies isolated from adenoids and PBMCs with the indicated neutralization potencies (n = 808 antibodies). b Pie charts show the distribution of memory B cell subsets from which neutralizing antibodies were isolated. The number in the center of the pie denotes the number of neutralizing antibodies. c Apparent binding affinities of adenoid-derived antibodies isolated from each memory B cell subset. d Neutralizing activity of adenoid-derived antibodies isolated from each memory B cell subset. Only antibodies with detectable binding and neutralizing activity are plotted. e Percentage of preF-specific, preF/postF-cross-reactive, or postF-specific antibodies with the indicated neutralization potencies. Antibodies from all donors were pooled for this analysis. f Pie charts show the percentage of highly potent neutralizing antibodies (IC50 ≤ 0.05 ug/ml) derived from either adenoids or PBMCs that are preF-specific, postF-specific, or preF/postF-cross-reactive. The number in the center of the pie denotes the number of highly potent neutralizing antibodies isolated from adenoids or PBMCs. Statistical comparisons were made using the Mann-Whitney test (n.s. = not significant). Results are representative of two independent experiments
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