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Proc Natl Acad Sci U S A. 2014 Sep 9;111(36):13139-44. doi: 10.1073/pnas.1409155111. Epub 2014 Aug 25.

Diversity and clonal selection in the human T-cell repertoire.

Author information

1
Divisions of Immunology and Rheumatology, Department of Medicine and.
2
Stanford Center for Biomedical Informatics Research, and Departments of Pathology.
3
Genetics, and.
4
Departments of Pathology, Immunology, Stanford University, Stanford, CA 94305; and.
5
Departments of Pathology.
6
Biostatistics.
7
Divisions of Immunology and Rheumatology, Department of Medicine and Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA 94306.
8
Divisions of Immunology and Rheumatology, Department of Medicine and Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA 94306 jgoronzy@stanford.edu.

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.

KEYWORDS:

T-cell homeostasis; adaptive immune responses; aging; immunosenescence

PMID:
25157137
PMCID:
PMC4246948
DOI:
10.1073/pnas.1409155111
[Indexed for MEDLINE]
Free PMC Article

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