Dynamics of Individual T Cell Repertoires: From Cord Blood to Centenarians

Abstract

The diversity, architecture, and dynamics of the TCR repertoire largely determine our ability to effectively withstand infections and malignancies with minimal mistargeting of immune responses. In this study, we have employed deep TCRβ repertoire sequencing with normalization based on unique molecular identifiers to explore the long-term dynamics of T cell immunity. We demonstrate remarkable stability of repertoire, where approximately half of all T cells in peripheral blood are represented by clones that persist and generally preserve their frequencies for 3 y. We further characterize the extremes of lifelong TCR repertoire evolution, analyzing samples ranging from umbilical cord blood to centenarian peripheral blood. We show that the fetal TCR repertoire, albeit structurally maintained within regulated borders due to the lower numbers of randomly added nucleotides, is not limited with respect to observed functional diversity. We reveal decreased efficiency of nonsense-mediated mRNA decay in umbilical cord blood, which may reflect specific regulatory mechanisms in development. Furthermore, we demonstrate that human TCR repertoires are functionally more similar at birth but diverge during life, and we track the lifelong behavior of CMV- and EBV-specific T cell clonotypes. Finally, we reveal gender differences in dynamics of TCR diversity constriction, which come to naught in the oldest age. Based on our data, we propose a more general explanation for the previous observations on the relationships between longevity and immunity.

Insights into immune system development and function from mouse T-cell repertoires

“…Whereas this observation has been confirmed by deep sequencing of human TCR repertoires (15,16), the precise form and time-resolved dynamics of VDJ recombination have not been assessed.…”

Antigen receptor repertoire profiling from RNA-seq data

“…The resulting libraries were sequenced with 100 bp paired-end reads on a HiSeq2500 using V4 chemistry (Illumina Inc., San Diego). The second portion of total RNA of each sample was used for the targeted TRA and TRB profiling as described 20 , using Illumina MiSeq paired end 150+150 bp sequencing.…”

“…To further verify the efficiency and specificity of extracting TCR CDR3 repertoires from RNA-seq data, we performed deep targeted profiling of TCR alpha (TRA) and beta (TRB) chain repertoires (TCR-seq) as described 20 and 100+100 bp paired-end RNA-seq for the same RNA samples, obtained from surgically resected melanoma specimens from two patients, SPX6730 (ileocecal lymph node metastasis) and SPX8151 (small intestine resection).…”

Untitled

“…It changes throughout a person's life, influenced by infections, vaccinations, microbiota composition and lifestyle [125][126][127][128]. First, the ratio of native to immune memory cells decreases with age, resulting in deteriorating immunological memory characteristics [129][130][131].…”

“…First, the ratio of native to immune memory cells decreases with age, resulting in deteriorating immunological memory characteristics [129][130][131]. The diversity of adaptive immunity receptors in infancy is similar across the population, but at older age differences become more visible mirroring the events that have occurred in person's immune system throughout life [127,128] …”