Rapid Turnover of Effector–Memory CD4+ T Cells in Healthy Humans

Macallan, Derek C.; Wallace, Diana L.; Zhang, Yan; Lara, Catherine de; Worth, Andrew; Ghattas, Hala; Griffin, George E.; Beverley, Peter C. L.; Tough, David F.

doi:10.1084/jem.20040341

Cited by 178 publications

(189 citation statements)

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“…Simulations predict sharp decline of effective clonal diversity. We simulated the population dynamics of human naive T cells as described in the text and Materials and Methods, based on experimental estimates of the Hayflick limit (22,29), the bias in thymic production of different T-cell clones (46,47), and the rates of thymopoeisis (9,18,19,21), T cell turnover (42,43,45), and telomere attrition (31,48). We set the bias in thymic production of different T cell clones to w = 0.01.…”

Section: Discussionmentioning

confidence: 99%

“…We predicted, using a population-dynamic modeling approach based on experimental data (18,21,22,28,29,31,38,42,43,(46)(47)(48), that the markedly lower effective clonal diversity found in elderly humans results from the fact that each T cell can divide for only a limited number of times before it reaches replicative senescence (or the Hayflick limit) (29,63) and is consequently eliminated (28,36,37). This, coupled to the facts that thymic production of new T cells declines substantially with age (11,18,19) and that T cells will undergo compensatory proliferation (38,40,64) to fill the empty homeostatic space created by the loss of senescent cells, leads to a sharp fall in effective clonal diversity at approximately the same time as was empirically observed (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, we define e t ðiÞ ¼ te 2t=T GðiÞ, with T = 33.33 yr (18) and t = 0.0017 d 21 (21). In addition, experiments indicate that the daily turnover rate of naive T cells in adult humans ranges from ∼0.1 to ∼0.2% (42)(43)(44). A much lower estimate of the T cell turnover rate was previously reported (62), but a mathematical model that fits the same experimental data much better yields an estimate that is consistent FIGURE 1.…”

Section: Effective Clonal Diversity Declines Sharply In Old Agementioning

confidence: 99%

“…We propose that over time this dynamic will cause a chain reaction of cell loss, which will suddenly drive most T cell clones to extinction. In the following, we will demonstrate, using stochastic numerical simulations based on experimental data (18,21,22,28,29,31,38,(42)(43)(44)(45)(46)(47)(48), that this model provides a plausible explanation for the sharp decline of effective clonal diversity observed in elderly humans.…”

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The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells

Ndifon

Dushoff

2016

The Journal of Immunology

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Having a large number of sufficiently abundant T cell clones is important for adequate protection against diseases. However, as shown in this paper and elsewhere, between young adulthood and >70 y of age the effective clonal diversity of naive CD4/CD8 T cells found in human blood declines by a factor of >10. (Effective clonal diversity accounts for both the number and the abundance of T cell clones.) The causes of this observation are incompletely understood. A previous study proposed that it might result from the emergence of certain rare, replication-enhancing mutations in T cells. In this paper, we propose an even simpler explanation: that it results from the loss of T cells that have attained replicative senescence (i.e., the Hayflick limit). Stochastic numerical simulations of naive T cell population dynamics, based on experimental parameters, show that the rate of homeostatic T cell proliferation increases after the age of ∼60 y because naive T cells collectively approach replicative senescence. This leads to a sharp decline of effective clonal diversity after ∼70 y, in agreement with empirical data. A mathematical analysis predicts that, without an increase in the naive T cell proliferation rate, this decline will occur >50 yr later than empirically observed. These results are consistent with a model in which exhaustion of the proliferative capacity of naive T cells causes a sharp decline of their effective clonal diversity and imply that therapeutic potentiation of thymopoiesis might either prevent or reverse this outcome.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Effective Clonal Diversity Declines Sharply In Old Agementioning

confidence: 99%

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The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells

Ndifon

Dushoff

2016

The Journal of Immunology

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“…In vivo labeling with stable isotopes in combination with appropriate mathematical analysis of these data provides a way to obtain T cell decay and production rates and to follow the fate of recently produced T cells. Data on stable isotope labeling of naïve and memory human T cells (18)(19)(20)(21)(22) are available, but several short-comings of these studies hamper their interpretation: (i) the short-term labeling period, which did not allow for sufficiently high labeling levels of naïve cells (19,21,22); and (ii) the lack of delabeling curves in long-term labeling studies (20), which would have shown whether recently produced T cells contribute to the T cell pool under investigation or rapidly disappear by death or activation; and (iii) the frequent use of the precursor-product relationship (20,23,24), leading to underestimation of the extent of T cell turnover (25). Using the precursor-product relationship one measures the net accrual of label and ignores the possibility that cells were produced and lost during the labeling period because of a short life span.…”

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Sparse production but preferential incorporation of recently produced naïve T cells in the human peripheral pool

Vrisekoop

Braber

Boer

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

201

327

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In mice, recent thymic emigrants (RTEs) make up a large part of the naïve T cell pool and have been suggested to be a distinct short-lived pool. In humans, however, the life span and number of RTEs are unknown. Although 2 H2O labeling in young mice showed high thymic-dependent daily naïve T cell production, long term upand down-labeling with 2 H2O in human adults revealed a low daily production of naïve T cells. Using mathematical modeling, we estimated human naïve CD4 and CD8 T cell half-lives of 4.2 and 6.5 years, respectively, whereas memory CD4 and CD8 T cells had half-lives of 0.4 and 0.7 year. The estimated half-life of recently produced naïve T cells was much longer than these average half-lives. Thus, our data are incompatible with a substantial short-lived RTE population in human adults and suggest that the few naïve T cells that are newly produced are preferentially incorporated in the peripheral pool. recent thymic emigrants ͉ T cell half-lives ͉ T cell production T he role of the thymus in HIV infection is still poorly understood (1, 2). On the one hand, thymic failure has been suggested to play a crucial role in CD4 T cell loss during HIV infection (3), and rapid thymic rebound has been proposed to be responsible for T cell reconstitution during anti-viral treatment (4). However, it has been argued that thymic output in adults might be too low to have a large impact on CD4 T cell depletion (5). In general, these issues are addressed with estimates of thymic output, naïve and memory T cell production rates, and life spans that are simply extrapolated from observations in mice, monkeys, and lymphopenic or irradiated humans (6-11).Naïve T cells are generally thought to turnover relatively slowly, but it has been suggested that, in mice, a considerable part of the naïve T cell pool consists of RTEs with relatively rapid turnover (9, 10, 12). In humans, naïve T cell numbers, T cell receptor excision circles (TRECs), and expression of CD31 have been used to measure thymic output (7,13,14). Dion et al. (4) observed rapid changes in the Sj/V␤ TREC ratio within 3 months after infection with HIV, which suggested the presence of a rapidly turning over RTE pool in human adults containing most of the TRECs in the periphery, similar to young rodents and chickens (15, 16). However, because TRECs are long-lived, none of these approaches is specific for T cells that have recently emigrated from the thymus (1, 2, 5), and, therefore, they fail to quantify thymic output in humans.Peripheral T cell proliferation might also contribute to the maintenance of the naïve T cell pool in human adults; however, it is unclear which fraction of these cells remains in the naïve T cell pool (17). The contribution of RTEs and peripheral T cell proliferation to the maintenance of the naïve T cell pool can only be determined by studying the fate of newly produced T cells. In vivo labeling with stable isotopes in combination with appropriate mathematical analysis of these data provides a way to obtain T cell decay and production rates ...

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Toward quantifying the usage costs of human immunity: Altered metabolic rates and hormone levels during acute immune activation in men

Muehlenbein

Hirschtick

Bonner

et al. 2010

American J Hum Biol

124

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There is a paucity of data on the energetic demands of human immune functions, despite the fact that both clinical medicine and evolutionary biology would benefit from further clarification of these costs. To better understand the energetic requirements of mounting a mild immune response, as well as some of the major hormonal changes underlying these metabolic changes, we examined changes in resting metabolic rate (RMR) and hormones during and after respiratory tract infection in young adult men. An epidemiologic passive detection design was used to recruit 25 nonfebrile subjects naturally infected with respiratory tract pathogens. Symptomology, percent body fat, RMR, salivary testosterone and cortisol, and other information were collected at a minimum of three time points during and after convalescence. Comparisons of the differences in RMR, testosterone, and cortisol between sampling days within individual cases were made using paired t-tests. Participants experienced 8% higher RMR during illness, and a subset of these men experienced a mean increase greater than 14%. The participants also experienced 10% lower testosterone levels during illness, and a subset of these participants experienced a mean decrease of 30%, although cortisol levels did not change significantly. These results document elevated RMR following natural pathogen exposure in adult humans, demonstrating that even mild immune reactions can elicit significant increases in energy expenditure. Understanding the costs of immunity and the immunomodulatory actions of hormones are central to understanding the role of immunity in human life history evolution.

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Rapid Turnover of Effector–Memory CD4+ T Cells in Healthy Humans

Cited by 178 publications

References 28 publications

The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells

The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells

Sparse production but preferential incorporation of recently produced naïve T cells in the human peripheral pool

Toward quantifying the usage costs of human immunity: Altered metabolic rates and hormone levels during acute immune activation in men

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