Lymphocyte maintenance during healthy aging requires no substantial alterations in cellular turnover

Westera, Liset; Hoeven, Vera van; Drylewicz, Julia; Spierenburg, Gerrit; Velzen, Jeroen F. van; Boer, Rob J. de; Tesselaar, Kiki; Borghans, José A. M.

doi:10.1111/acel.12311

Cited by 85 publications

(154 citation statements)

References 49 publications

(77 reference statements)

Supporting

Mentioning

137

Contrasting

Order By: Relevance

“…2A). This observed increase in the T cell proliferation rate is in general agreement with empirical data showing that, in comparison with young adults, the naive T cell turnover rate in elderly humans either doubles (9) or does not change significantly in the CD4 compartment (65), and it increases by ∼3-fold in the CD8 compartment (65). An increase in T cell proliferation at old age has also been observed in rhesus macaques (7).…”

Section: Discussionsupporting

confidence: 90%

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

Ndifon

Dushoff

2016

The Journal of Immunology

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 90%

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

Ndifon

Dushoff

2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…As thymic export stops or diminishes, the maintaining peripheral T cell pool proliferates, replenishing the peripheral space and gradually acquiring an effector/memory phenotype, as also seen in lymphopenic conditions and aging (8,9,13,30). This slowly results in the loss of naive T cells and skewing toward the effector/memory phenotype.…”

Section: Discussionmentioning

confidence: 98%

“…After the first year of life, naive T cell production in the thymus starts to decline, resulting in a very minimal production rate in healthy adults (3)(4)(5)(6). Even though the adult thymus is still able to produce new naive T cells (7,8), we and others have shown that, in contrast to what is seen in mice, most of the naive T cell population in humans is maintained by homeostatic proliferation (9,10). Due to increased homeostatic proliferation or decreased cell death, only a marginal decrease of the overall size of the naive T cell pool is observed during aging (11)(12)(13)(14)(15).…”

Section: Ccr7mentioning

confidence: 99%

Neonatal thymectomy reveals differentiation and plasticity within human naive T cells

Broek¹,

Delemarre²,

Janssen³

et al. 2016

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

“…Naïve CD4 + T-cells feature low levels of proliferation while maintaining their naïve phenotype, as demonstrated by studies using in vivo incorporation of deuterated water or Bromodeoxyuridine (BrdU) (7, 84, 85). It remains unclear whether naïve cell turnover changes with age (8, 77, 86, 87), as well as with the time span since thymic egress (2, 8, 76).…”

Section: Thymic Versus Peripheral Contribution For Naïve Cd4+ T-cell mentioning

confidence: 99%

Establishment and Maintenance of the Human Naïve CD4+ T-Cell Compartment

Silva¹,

Sousa

2016

Front. Pediatr.

View full text Add to dashboard Cite

The naïve CD4+ T-cell compartment is considered essential to guarantee immune competence throughout life. Its replenishment with naïve cells with broad diverse receptor repertoire, albeit with reduced self-reactivity, is ensured by the thymus. Nevertheless, cumulative data support a major requirement of post-thymic proliferation both for the establishment of the human peripheral naïve compartment during the accelerated somatic growth of childhood, as well as for its lifelong maintenance. Additionally, a dynamic equilibrium is operating at the cell level to fine-tune the T-cell receptor threshold to activation and survival cues, in order to counteract the continuous naïve cell loss by death or conversion into memory/effector cells. The main players in these processes are low-affinity self-peptide/MHC and cytokines, particularly IL-7. Moreover, although naïve CD4+ T-cells are usually seen as a homogeneous population regarding stage of maturation and cell differentiation, increasing evidence points to a variety of phenotypic and functional subsets with distinct homeostatic requirements. The paradigm of cells committed to a distinct lineage in the thymus are the naïve regulatory T-cells, but other functional subpopulations have been identified based on their time span after thymic egress, phenotypic markers, such as CD31, or cytokine production, namely IL-8. Understanding the regulation of these processes is of utmost importance to promote immune reconstitution in several clinical settings, namely transplantation, persistent infections, and aging. In this mini review, we provide an overview of the mechanisms underlying human naïve CD4+ T-cell homeostasis, combining clinical data, experimental studies, and modeling approaches.

show abstract

Lymphocyte maintenance during healthy aging requires no substantial alterations in cellular turnover

Cited by 85 publications

References 49 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

Neonatal thymectomy reveals differentiation and plasticity within human naive T cells

Establishment and Maintenance of the Human Naïve CD4+ T-Cell Compartment

Contact Info

Product

Resources

About