Diversity and clonal selection in the human T-cell repertoire

Abstract

T-cell receptor (TCR) diversity, a prerequisite for immune system recognition of the universe of foreign antigens, is generated in the first two decades of life in the thymus and then persists to an unknown extent through life via homeostatic proliferation of naïve T cells. We have used next-generation sequencing and nonparametric statistical analysis to estimate a lower bound for the total number of different TCR beta (TCRB) sequences in human repertoires. We arrived at surprisingly high minimal estimates of 100 million unique TCRB sequences in naïve CD4 and CD8 T-cell repertoires of young adults. Naïve repertoire richness modestly declined two-to fivefold in healthy elderly. Repertoire richness contraction with age was even less pronounced for memory CD4 and CD8 T cells. In contrast, age had a major impact on the inequality of clonal sizes, as estimated by a modified Gini-Simpson index clonality score. In particular, large naïve T-cell clones that were distinct from memory clones were found in the repertoires of elderly individuals, indicating uneven homeostatic proliferation without development of a memory cell phenotype. Our results suggest that a highly diverse repertoire is maintained despite thymic involution; however, peripheral fitness selection of T cells leads to repertoire perturbations that can influence the immune response in the elderly.adaptive immune responses | aging | immunosenescence | T-cell homeostasis T he ability of the adaptive immune system to respond to a wide variety of pathogens depends on a large repertoire of unique T-cell receptors (TCRs). TCR diversity is generated by the random and imprecise rearrangements of the V and J segments of the TCR alpha (TCRA) and V, D, and J segments of the TCR beta (TCRB) genes in the thymus. Thymic production of T cells is the sole mechanism to generate TCR diversity. With

The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells

“…Data obtained from a variety of species (6)(7)(8)(9)(10)(11)16) indicate that the effective clonal diversity of T cells declines with age. Using CDR3 amino acid sequences obtained from the TCR b-chain (16), we estimated the age-dependent change in the effective clonal diversity of naive CD4/CD8 T cells found in human blood (Fig.…”

“…The diversity of the CDR3 region might be affected by an individual's gender as well as by chronic infections, most notably CMV. We obtained the results reported in this paper using CDR3 amino acid sequences collected by Goronzy and coworkers (16), which came from four younger and five older individuals. The genders of these individuals are unknown, so we cannot evaluate the potential effect of gender on our estimates of diversity.…”

“…Effective clonal diversity of naive T cells declines with age. We used five replicate TCRB CDR3 amino acid sequence datasets (16) from both naive CD4 (left panel) and CD8 (right panel) T cells to estimate effective clonal diversity (Materials and Methods). r denotes the correlation coefficient between effective clonal diversity and age.…”

“…For human naive T cells, TCR sequence data (9,11,16) indicate that their effective clonal diversity (defined as the reciprocal of the probability that two randomly chosen T cells belong to the same clone) (17) declines sharply after the age of ∼70 years. Note that in contrast to measures of diversity that account only for the number of different T cell clones, effective clonal diversity accounts also for clone frequencies.…”

Characteristics of the TCR Vβ repertoire in imatinib-resistant chronic myeloid leukemia patients with ABL mutations

“…This diversity is prerequisite for guaranteeing that an organism can fight against a universe of foreign antigens and maintain a balanced immune status. The human T cell system is estimated to contain approximately 3×10 11 cells, which results in estimates for TCR  chain diversity for young adults in the range of 2×10 6 to 2×10 7 cells, and each TCR  chain can combine with 25 or more TCR  chains [12,13]. T cell clone diversity originates from T cell differentiation in the thymus, which is characterized by the formation of the complementarity-determining region (CDR) according to rearrangement of multiple variable (V), diversity (D), and joining (J) gene segments.…”