Age-Related Decrease in TCR Repertoire Diversity Measured with Deep and Normalized Sequence Profiling

Abstract

The decrease of TCR diversity with aging has never been studied by direct methods. In this study, we combined high-throughput Illumina sequencing with unique cDNA molecular identifier technology to achieve deep and precisely normalized profiling of TCR β repertoires in 39 healthy donors aged 6–90 y. We demonstrate that TCR β diversity per 106 T cells decreases roughly linearly with age, with significant reduction already apparent by age 40. The percentage of naive T cells showed a strong correlation with measured TCR diversity and decreased linearly up to age 70. Remarkably, the oldest group (average age 82 y) was characterized by a higher percentage of naive CD4+ T cells, lower abundance of expanded clones, and increased TCR diversity compared with the previous age group (average age 62 y), suggesting the influence of age selection and association of these three related parameters with longevity. Interestingly, cross-analysis of individual TCR β repertoires revealed a set >10,000 of the most representative public TCR β clonotypes, whose abundance among the top 100,000 clones correlated with TCR diversity and decreased with aging.

Effects of aging on human leukocytes (part II): immunophenotyping of adaptive immune B and T cell subsets

“…However, the diversity of the naïve T cell compartment decreases with age. Deep sequencing of the complementarity-determining region 3 of the T cell receptor (TCR)-β chain from healthy donors revealed that the fraction of expanded clones increases with age (Britanova et al 2014). Similarly, spectratyping of the TCRVB genes revealed the expansion of particular segments (Pennesi et al 2001).…”

Immunosenescence and hurdles in the clinical management of older HIV-patients

“…29,34,37 This finding in addition to developmental and signaling alterations alongside with age-related decrease in T-cell generation are all found in cells from older adults, which contribute to functional deficits. The altered signaling is fostered by the persistence of low quantity of pro-inflammatory cytokines and increased production of ROS, both characteristics of InflammAging.…”

A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4+T cell receptor repertoire clonality

“…In contrast, as CI approaches 1, this indicates a clonal TCR or BCR repertoire, or increased expansion of certain clones in the repertoire. A measure of relative clonotype richness R was also calculated as the average unique clonotypes per cell (assuming one unique clonotype per cell), given by 35 …”

“…35 Using ultra-deep sequencing, the authors revealed that diversity of T cell clonotypes decreased almost linearly with age. In addition, there was a significant negative correlation of age with the percentage of na€ ıve T cells in peripheral blood, though this trend was most pronounced up to subjects age 70.…”

“…In addition, there was a significant negative correlation of age with the percentage of na€ ıve T cells in peripheral blood, though this trend was most pronounced up to subjects age 70. 35 Therefore age-related immunosenescene may be the major mechanism responsible for the difference of CD4 C T cell clonality between younger and older patients. The underlying mechanisms of immunosenescene of T cells can be traced back to thymic involution with aging.…”