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  • Review Article
  • Published:

Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections

Nature Reviews Immunology volume 8, pages 512–522 (2008)Cite this article

Key Points

  • A decline in T-cell immunity is one of the most consistent and most profound deficiencies of the elderly. Therapeutic correction of this decline often restores immune responsiveness and immune defence.

  • T-cell immune decline in the elderly has at least two underpinnings: a drop in the responsiveness of naive T cells to stimulation (cell-autonomous defects) and a reduction in naive T-cell numbers and diversity that leads to a dominant memory T-cell pool (T-cell population imbalance).

  • This article discusses two key causes of age-related T-cell population imbalance: homeostatic cycling or proliferative expansion in the peripheral T-cell pool, and latent persistent infections, which repeatedly stimulate the T-cell pool over the lifetime of the individual.

  • The reduction in production of naive T cells by the thymus forces the ageing organism to rely on compensatory homeostatic mechanisms to maintain the balance between naive and memory T-cell pools. Although this may be initially successful, recent evidence suggests that late in life these mechanisms exhaust their usefulness and actually contribute to a further demise of the remaining naive T cells.

  • Latent persistent infections, particularly with herpesviruses, lead to life-long periodic restimulation of the immune system, here, evidence is presented for the role of viral reactivation in this restimulation using a mouse model of herpesvirus infection and ageing.

  • Relative roles and the interplay between the homeostatic and viral factors are discussed, with the former having a surprisingly prominent role. Finally, modes of immune rejuvenation and anti-ageing intervention are debated in light of these advances in our knowledge.

Abstract

A diverse and well-balanced repertoire of T cells is thought to be crucial for the efficacious defence against infection with new or re-emerging pathogens throughout life. In the last third of the mammalian lifespan, the maintenance of a balanced T-cell repertoire becomes highly challenging because of the changes in T-cell production and consumption. In this Review, I question whether latent persistent pathogens might be key factors that drive this imbalance and whether they determine the extent of age-associated immune deficiency.

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Figure 1: T-cell homeostasis.
Figure 2: Cellular and population-based changes in T-cell senescence.
Figure 3: Disruption of T-cell homeostasis with ageing: possible causes.
Figure 4: Adding insult to injury: the impact of persistent pathogens on T-cell population dynamics with age.
Figure 5: Persistent viruses and their antigenic load over time.

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Acknowledgements

I thank the members of my laboratory for stimulating discussions (in particular, L. Cicin-Sain, A. Lang and B. Rudd) and A. Townsend for help with the original illustrations. I also acknowledge support from the US Public Health Service awards AG20719, AG21384, AG23664 and N0150027 from the National Institute on Aging and National Institute of Allergy and Infectious Diseases and RR 0163 (the Core National Primate Research Center award to Oregon National Primate Research Centre) from the National Institutes of Health, USA.

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  1. Department of Immunobiology and the Arizona Center on Aging, University of Arizona, Tucson, 85724, Arizona, USA

    Janko Nikolich-Žugich

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Glossary

Oxidative stress

The cellular state in which there is an imbalance between the production and neutralization of reactive oxygen species (ROS), such as H2O2, OH−, HOO− and superoxide. Excess ROS can generate oxidative reactions that can result in disrupted cellular signalling, injury and death.

Non-homologous end-joining

A pathway that rejoins DNA strand breaks without relying on significant homology. The main known pathway uses the Ku-end binding complex and is regulated by DNA protein kinase. The pathway is often used in mammalian cells to repair strand breaks caused by DNA-damaging agents, and some of the same enzymes are used during the strand-joining steps of V(D)J recombination.

Thymic involution

The age-dependent decrease of thymic epithelial volume and decreased production of T cells.

T-cell homeostasis

The maintenance of relatively stable numbers of naive and memory T cells and of balanced T-cell receptor diversity, as well as the ability of the T-cell pool to restore these numbers and diversity to prior resting state after acute antigen challenge.

Common cytokine-receptor γ-chain family

A family of cytokine receptors in which each receptor complex is composed of two or three subunits, with one of those subunits being the common cytokine-receptor γ-chain (γc).

Regulatory T cells

A subset of CD4+ T cells that has suppressive regulatory activity towards effector T cells and other immune cells. This subset includes cells that express high levels of CD25 (the interleukin-2 receptor α-chain) and the transcription factor forkhead box P3 (FOXP3). Other regulatory T-cell populations can be CD25−FOXP3− and produce the regulatory cytokine interleukin-10, which suppresses the functions of T-helper-1-type effector T cells and other immune cells. The absence or dysfunction of regulatory T cells is associated with severe autoimmunity.

Central memory T cells

Antigen-experienced CD8+ T cells that lack immediate effector function but can mediate rapid recall responses by virtue of quick and sustained cell division and rapid development into effector or effector memory cells after restimulation with antigen. Central memory T cells retain the migratory properties of naive cells and therefore circulate through the secondary lymphoid organs.

Effector memory T cells

Terminally differentiated T cells that lack most, but not all, lymph-node homing receptors, but express receptors that enable them to home to inflamed tissues. Effector memory cells contain perforin and can exert immediate effector functions without the need of further differentiation.

Specific pathogen free (SPF) conditions

Vivarium conditions for rodents whereby an increasing number of pathogens are excluded or eradicated from the colony. These animals are maintained in the absence of most of the known chronic and latent persistent pathogens. Although this enables better control of experimental conditions related to immunity and infection, it also sets apart such animal models from pathogen-exposed humans or non-human primates, whose immune systems are in constant contact with infection.

MHC class I tetramers

Biotinylated monomeric MHC molecules that are folded with a specific peptide in the binding groove and tetramerized with a fluorescently labelled streptavidin molecule. These tetramers will bind to T cells that express T-cell receptors specific for the cognate peptide, allowing direct enumeration of antigen-specific T cells.

Clonal exhaustion

A state of non-reactivity in which all precursor lymphocytes responding to persistent antigen(s) differentiate into effector cells which are driven into the state of functional exhaustion, such that they no longer can productively engage and control the pathogen. The end result of clonal exhaustion is purging the immune-response repertoire of a particular specificity (or specificities).

Bromodeoxyuridine

(5-Bromo-2-deoxyuridine; BrdU). A thymidine analogue that is incorporated into DNA on replication, allowing tracking of cells that have divided using BrdU-specific antibodies and flow cytometry.

Immune risk phenotype

A set of empirical immune system (mainly T-cell) measurements that are thought to be biomarkers (although in some circumstances this still needs to be verified) of immune senescence. These include: reduced naive T-cell numbers, inverted CD4:CD8 ratios (>1 in youth, ≥1 in ageing), accumulation of CD28− (effector memory) T cells, reduced proliferative ability, reduced interleukin-2 production and presence of cytomegalovirus infection.

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Nikolich-Žugich, J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol 8, 512–522 (2008). https://doi.org/10.1038/nri2318

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