Dramatic increase in naive T cell turnover is linked to loss of naive T cells from old primates.
The loss of naïve T cells is a hallmark of immune aging. Although thymic involution is a primary driver of this naïve T cell loss, less is known about the contribution of other mechanisms to the depletion of naïve T cells in aging primates. We examined the role of homeostatic cycling and proliferative expansion in different T cell subsets of aging rhesus macaques (RM). BrdU incorporation and the expression of the G(1)-M marker Ki-67 were elevated in peripheral naïve CD4 and even more markedly in the naïve CD8 T cells of old, but not young adult, RM. Proliferating naïve cells did not accumulate in old animals. Rather, the relative size of the naïve CD8 T cell compartment correlated inversely to its proliferation rate. Likewise, T cell receptor diversity decreased in individuals with elevated naïve CD8 T cell proliferation. This apparent contradiction was explained by a significant increase in turnover concomitant with the naïve pool loss. The turnover increased exponentially when the naïve CD8 T cell pool decreased below 4% of total blood CD8 cells. These results link the shrinking naïve T cell pool with a dramatic increase in homeostatic turnover, which has the potential to exacerbate the progressive exhaustion of the naïve pool and constrict the T cell repertoire. Thus, homeostatic T cell proliferation exhibits temporal antagonistic pleiotropy, being beneficial to T cell maintenance in adulthood but detrimental to the long-term T cell maintenance in aging individuals.
Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA.
Luka
L
Cicin-Sain
Ilhem
I
Messaoudi
Byung
B
Park
Noreen
N
Currier
Shannon
S
Planer
Miranda
M
Fischer
Shane
S
Tackitt
Dragana
D
Nikolich-Zugich
Alfred
A
Legasse
Michael K
MK
Axthelm
Louis J
LJ
Picker
Motomi
M
Mori
Janko
J
Nikolich-Zugich
D000375:Aging / Q000276:immunology*; D000818:Animals; D049109:Cell Proliferation; D005260:Female; D006706:Homeostasis / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D019394:Ki-67 Antigen / Q000378:metabolism; D007700:Kinetics; D008253:Macaca mulatta / Q000276:immunology*; D008297:Male; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
D019394:Ki-67 Antigen