Dramatic increase in naïve T cell turnover is linked to loss of naïve T cells from old primates

Luka Čičin-Šain, Ilhem Messaoudi, Byung Park, Noreen Currier, Shannon Planer, Miranda Fischer, Shane Tackitt, Dragana Nikolich-Žugich, Alfred Legasse, Michael K. Axthelm, Louis J. Picker, Motomi Mori, Janko Nikolich-Zugich

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

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 G1-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 na?̈ve 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.

Original languageEnglish (US)
Pages (from-to)19960-19965
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number50
DOIs
StatePublished - Dec 11 2007
Externally publishedYes

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Primates
T-Lymphocytes
Cell Aging
Macaca mulatta
Maintenance
Cell Proliferation
T-Lymphocyte Subsets
Bromodeoxyuridine
T-Cell Antigen Receptor
Young Adult
Blood Cells

Keywords

  • Aging
  • CD8
  • Homeostasis

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Dramatic increase in naïve T cell turnover is linked to loss of naïve T cells from old primates. / Čičin-Šain, Luka; Messaoudi, Ilhem; Park, Byung; Currier, Noreen; Planer, Shannon; Fischer, Miranda; Tackitt, Shane; Nikolich-Žugich, Dragana; Legasse, Alfred; Axthelm, Michael K.; Picker, Louis J.; Mori, Motomi; Nikolich-Zugich, Janko.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 50, 11.12.2007, p. 19960-19965.

Research output: Contribution to journalArticle

Čičin-Šain, L, Messaoudi, I, Park, B, Currier, N, Planer, S, Fischer, M, Tackitt, S, Nikolich-Žugich, D, Legasse, A, Axthelm, MK, Picker, LJ, Mori, M & Nikolich-Zugich, J 2007, 'Dramatic increase in naïve T cell turnover is linked to loss of naïve T cells from old primates', Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 50, pp. 19960-19965. https://doi.org/10.1073/pnas.0705905104
Čičin-Šain, Luka ; Messaoudi, Ilhem ; Park, Byung ; Currier, Noreen ; Planer, Shannon ; Fischer, Miranda ; Tackitt, Shane ; Nikolich-Žugich, Dragana ; Legasse, Alfred ; Axthelm, Michael K. ; Picker, Louis J. ; Mori, Motomi ; Nikolich-Zugich, Janko. / Dramatic increase in naïve T cell turnover is linked to loss of naïve T cells from old primates. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 50. pp. 19960-19965.
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abstract = "The loss of na{\"i}ve T cells is a hallmark of immune aging. Although thymic involution is a primary driver of this na{\"i}ve T cell loss, less is known about the contribution of other mechanisms to the depletion of na{\"i}ve 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 G1-M marker Ki-67 were elevated in peripheral na{\"i}ve CD4 and even more markedly in the na{\"i}ve CD8 T cells of old, but not young adult, RM. Proliferating na?̈ve cells did not accumulate in old animals. Rather, the relative size of the na{\"i}ve CD8 T cell compartment correlated inversely to its proliferation rate. Likewise, T cell receptor diversity decreased in individuals with elevated na{\"i}ve CD8 T cell proliferation. This apparent contradiction was explained by a significant increase in turnover concomitant with the na{\"i}ve pool loss. The turnover increased exponentially when the na{\"i}ve CD8 T cell pool decreased below 4{\%} of total blood CD8 cells. These results link the shrinking na{\"i}ve T cell pool with a dramatic increase in homeostatic turnover, which has the potential to exacerbate the progressive exhaustion of the na{\"i}ve 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.",
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