Diversity and clonal selection in the human T-cell repertoire

Qian Qi, Yi Liu, Yong Cheng, Jacob Glanville, David Zhang, Ji Yeun Lee, Richard A. Olshen, Cornelia M. Weyand, Scott D. Boyd, Jörg J. Goronzy

Research output: Contribution to journalArticlepeer-review

297 Scopus citations

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 non-parametric 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 five fold 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.

Original languageEnglish (US)
Pages (from-to)13139-13144
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number36
DOIs
StatePublished - 2014

Keywords

  • Adaptive immune responses
  • Aging
  • Immunosenescence
  • T-cell homeostasis

ASJC Scopus subject areas

  • General

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