The influence of age on T cell generation and TCR diversity.
The ability to mount protective immune responses depends on the diversity of T cells. T cell diversity may be compromised by the declining thymic output of new T cells. The aging process imposes a threat to diversity, because thymic function deteriorates. In this study we have examined the relationship between thymic production, homeostatic T cell proliferation and TCR beta-chain diversity in young (approximately 25 years), middle-aged ( approximately 60 years), and elderly adults (approximately 75 years). TCR excision circles (TREC) as a marker of thymic output exponentially decreased by >95% between 25 and 60 years of age. The frequency of Ki67(+) cycling CD4 T cells remained steady, and surprisingly, the diversity of the naive CD4 T cell repertoire was maintained at approximately 2 x 10(7) different TCR beta-chains. After the age of 70 years, TRECs only slightly declined, but homeostatic proliferation doubled. The diversity of the T cell pool drastically contracted to 200,000 TCR beta-chains. Also, the phenotypic distinction between naive and memory CD4 T cells became fuzzy. The collapse in CD4 T cell diversity during the seventh and eighth decades indicates substantial T cell loss and implies that therapeutic measures to improve vaccine responses will have to include strategies for T cell replenishment.
Naylor
Keith
K
Department of Medicine, Mayo Clinic and Graduate School, Rochester, MN 55905, USA.
Li
Guangjin
G
Vallejo
Abbe N
AN
Lee
Won-Woo
WW
Koetz
Kerstin
K
Bryl
Ewa
E
Witkowski
Jacek
J
Fulbright
James
J
Weyand
Cornelia M
CM
Goronzy
Jörg J
JJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism / Q000502:physiology
D011948:Receptors, Antigen, T-Cell