B-cell repertoire responses to varicella-zoster vaccination in human identical twins

Abstract

Adaptive immune responses in humans rely on somatic genetic rearrangements of Ig and T-cell receptor loci to generate diverse antigen receptors. It is unclear to what extent an individual's genetic background affects the characteristics of the antibody repertoire used in responding to vaccination or infection. We studied the B-cell repertoires and clonal expansions in response to attenuated varicella-zoster vaccination in four pairs of adult identical twins and found that the global antibody repertoires of twin pair members showed high similarity in antibody heavy chain V, D, and J gene segment use, and in the length and features of the complementarity-determining region 3, a major determinant of antigen binding. These twin similarities were most pronounced in the IgM-expressing B-cell pools, but were seen to a lesser extent in IgG-expressing B cells. In addition, the degree of antibody somatic mutation accumulated in the B-cell repertoire was highly correlated within twin pair members. Twin pair members had greater numbers of shared convergent antibody sequences, including mutated sequences, suggesting similarity among memory B-cell clonal lineages. Despite these similarities in the memory repertoire, the B-cell clones used in acute responses to ZOSTAVAX vaccination were largely unique to each individual. Taken together, these results suggest that the overall B-cell repertoire is significantly shaped by the underlying germ-line genome, but that stochastic or individual-specific effects dominate the selection of clones in response to an acute antigenic stimulus.

Keywords: B cell repertoire; Varicella Zoster vaccine; antibody; convergent; twin.

Conflict of interest statement

Conflict of interest statement: Scott Boyd has consulted for Immumetrix, Inc., now part of CareDx, Inc., on topics distinct from those in the current manuscript.

Figures

Fig. 1.

Antibody responses, plasmablast counts, and clonal expansion postvaccination. (A) The anti-VZV activity in the serum was expressed as a ratio of anti-VZV titer on day 28/day 0. (B) Plasmablasts as a percentage of total CD3− CD19+ B cells on days 0 (prevaccination), 8, 14, and 28 postvaccination. Samples from twin pair members are labeled with the same colors, with each individual within the twin pair labeled with a different symbol: twins A (red), twins B (green), twins C (blue), and twins D (purple). (C) Day 8 B-cell clonal expansion differs between twin pair members. Clonality score of gDNA sequences from each sample was calculated from six independent gDNA replicates. The x axis indicates the number of days postvaccination.

Fig. 2.

IGHV, IGHD, and IGHJ gene use is highly correlated within twin pairs. Correlation heatmap of use of V (A), D (B), and J (C) gene segments in the IgH of all samples, using gDNA template. Each square represents the correlation of gene segment use of two samples. Four samples from each individual are positioned sequentially in the order of time points (d0, d8, d14, and d28 from left to right in the x axis and from top to bottom in the y axis) for the eight individuals as labeled in the figure (A1, A2, B1, B2, C1, C2, D1, and D2 from left to right in the x axis and from top to bottom in the y axis). Correlations were calculated as Pearson correlations, using all V, D, or J gene segments identified in the data, without regard for allelic variants. The colored scale bar represents the strength of correlation of each sample pair.

Fig. 3.

CDR3 length and IGHV mutation of functional gDNA is highly correlated within twin pairs. (A) Mean CDR3 of nonfunctional or functional sequences, and mutated or nonmutated sequences in the functional category on different days. (B) Median V-mutation frequency of the mutated sequences. (C) Samples from the same twin pairs of different time points form clusters on the 2D presentation of mean CDR3 and median V-mutation. Members of the same twin pair are labeled with the same color, and the two individuals from each twin pair are labeled with different symbols.

Fig. 4.

CDR3 lengths of IgM are correlated within twin pairs. Mean CDR3 length of IgM functional sequences (A), nonmutated (B) or mutated (C), and functional IgG (D) sequences. Twin pair C is blue and twin pair D is purple.

Fig. 5.

IGHV mutation frequencies of convergent clones are affected by twin status. Average V-mutation frequencies of clones convergent between sample pairs from unrelated individuals (A), from within twin-pair members (B), and between different time point samples from the same individual (C).