Distinctive properties of identical twins' TCR repertoires revealed by high-throughput sequencing

Abstract

Adaptive immunity in humans is provided by hypervariable Ig-like molecules on the surface of B and T cells. The final set of these molecules in each organism is formed under the influence of two forces: individual genetic traits and the environment, which includes the diverse spectra of alien and self-antigens. Here we assess the impact of individual genetic factors on the formation of the adaptive immunity by analyzing the T-cell receptor (TCR) repertoires of three pairs of monozygous twins by next-generation sequencing. Surprisingly, we found that an overlap between the TCR repertoires of monozygous twins is similar to an overlap between the TCR repertoires of nonrelated individuals. However, the number of identical complementary determining region 3 sequences in two individuals is significantly increased for twin pairs in the fraction of highly abundant TCR molecules, which is enriched by the antigen-experienced T cells. We found that the initial recruitment of particular TCR V genes for recombination and subsequent selection in the thymus is strictly determined by individual genetic factors. J genes of TCRs are selected randomly for recombination; however, the subsequent selection in the thymus gives preference to some α but not β J segments. These findings provide a deeper insight into the mechanism of TCR repertoire generation.

Keywords: TCR repertoire analysis; immunogenetics; twin studies.

Fig. 1.

JS divergence for Vβ, Jβ and Vα, Jα segment usage of out-of-frame clonotypes. Each column indicates the JS divergence divided by the mean entropy (for each pair) between an individual and five other individuals. Error bars indicate SD calculated using the bootstrap analysis. Red circles, individuals A1 or A2; blue circles, individuals C1 or C2; green circles, individuals D1 or D2.

Fig. 2.

JS divergence for Vβ, Jβ and Vα, Jα segment usage of in-frame clonotypes. Each column indicates the JS divergence divided by the mean entropy (for each pair) between an individual and five other individuals. Error bars indicate SD calculated using the bootstrap analysis. Red circles, individuals A1 or A2; blue circles, individuals C1 or C2; green circles, individuals D1 or D2.

Fig. 3.

Correlation between the number of shared clonotypes in each pair of individuals and the product of intersected cloneset sizes. Red circles correspond to twin pairs, and black circles correspond to unrelated pairs. Empty triangles correspond to the number of shared clonotypes obtained for two pairs of individuals by Warren et al. (6). Dash lines indicate the 98% prediction intervals for both regression lines.

Fig. 4.

The normalized number of identical TCRβ CDR3 amino acid sequences for each possible pair of individuals among 1,000 most abundant clonotypes, 2,000 most abundant clonotypes, etc. x axis, the number of the most abundant clonotypes (×1,000) intersected; y axis, the normalized number of shared clonotypes. The shaded area (orange) indicates the mean ± SD calculated for pairs formed by twin with each unrelated individual.

Fig. 5.

The percentage of clonotypes with identical CDR3 amino acid sequences sharing the same V gene for all possible pairs of individuals. Black circles indicate twin pairs, empty circles indicate all other pairs, and lines indicate median values. β all, among all identified TCRβ clonotypes; α all, among all identified TCRα clonotypes, β top 10K, among 10,000 most abundant TCRβ clonotypes; α top 10K, among 10,000 most abundant TCRα clonotypes.