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Mechanisms underlying T cell ageing

Abstract

T cell ageing has a pivotal role in rendering older individuals vulnerable to infections and cancer and in impairing the response to vaccination. Easy accessibility to peripheral human T cells as well as an expanding array of tools to examine T cell biology have provided opportunities to examine major ageing pathways and their consequences for T cell function. Here, we review emerging concepts of how the body attempts to maintain a functional T cell compartment with advancing age, focusing on three fundamental domains of the ageing process, namely self-renewal, control of cellular quiescence and cellular senescence. Understanding these critical elements in successful T cell ageing will allow the design of interventions to prevent or reverse ageing-related T cell failure.

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Fig. 1: Successful T cell replenishment by self-renewal.
Fig. 2: Mechanisms compromising T cell homeostasis.
Fig. 3: Activation of differentiation pathways in T cell ageing.
Fig. 4: Relationship between T cell differentiation and cellular senescence in T cell ageing.
Fig. 5: Regulation of cytokine transcription in effector T cells, TEMRA cells and senescent T cells.

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Acknowledgements

This work was supported by the US National Institutes of Health (R01 AR042527, R01 HL117913, R01 AI108906, R01 HL142068, and P01 HL129941 to C.M.W. and R01 AI108891, R01 AG045779, U19 AI057266, R01 AI129191, and I01 BX001669 to J.J.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Nature Reviews Immunology thanks J. Lord, B. Seddon and N.-P. Weng for their contribution to the peer review of this work.

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Correspondence to Jörg J. Goronzy.

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Glossary

Quiescence

A phase in the cell cycle in which the cell is not dividing or preparing to divide but still has the ability to do so in the presence of an appropriate signal. Quiescent cells have low metabolic activity and reduced protein synthesis.

Senescence

A cellular state in which an irreversible growth arrest programme has been initiated that limits the lifespan of the cell and prevents unlimited cell proliferation. It can be caused by replication-induced telomere shortening or DNA damage. In contrast to quiescent cells, senescent cells have a secretory phenotype and upregulated protein synthesis.

Exhaustion

Refers to an impaired ability of effector T cells to carry out their functions, such as cytotoxicity and cytokine secretion, owing to chronic stimulation by antigen.

Homeostatic proliferation

A process of activation and proliferation of lymphocytes in the lymphopenic environment. T cell homeostatic proliferation is driven by T cell receptor interactions with self-peptide–MHC and T cell responses to cytokines such as IL-7, IL-15 and possibly IL-21.

Virtual memory T cells

Antigen-inexperienced memory-phenotype T cells, which may be induced by T cell receptor cross reactivity, low-affinity peptide and/or MHC ligands and certain cytokines.

Fibroblastic reticular cells

(FRCs). Specialized reticular fibroblasts located in the T cell areas of lymph nodes and other secondary lymphoid organs. They provide IL-7 for T cell survival and produce collagen-rich reticular fibres and form stromal networks and conduits that are important for the trafficking of immune cells.

TCR excision circles

Small, stable circles of DNA excised during T cell receptor gene rearrangement in the thymus.

T effector memory CD45RA cells

(TEMRA cells). Terminally differentiated antigen-specific memory T cells that re-express CD45RA. These cells have been identified in both CD4+ and CD8+ T cell compartments, have short telomeres, exhibit cell cycle arrest, express DNA damage foci and have a secretome reminiscent of senescent cells.

Memory inflation

The gradual accumulation of peptide-specific CD8+ T cells with an effector memory phenotype that occurs after the resolution of certain acute viral infections during viral latency (for example, cytomegalovirus infection). Induction in the setting of chronic antigen persistence suggests the clonal expansion is antigen driven and not mutation driven.

Stem cell-like memory T cells

A subset of memory T cells that has naive-like features and phenotypes including enhanced self-renewal and multifunctional capacity.

DNA damage responses

A cell response triggered by DNA damage such as single or double strand breaks. The DNA damage response stops cell cycle progression to enable repair before the damage is transmitted to progeny cells. Checkpoints in the mammalian DNA damage response are controlled by the phosphoinositide 3-kinase-related kinases ATM and ATR.

Senolytics

Pharmacological compounds that preferentially deplete senescent cells.

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Goronzy, J.J., Weyand, C.M. Mechanisms underlying T cell ageing. Nat Rev Immunol 19, 573–583 (2019). https://doi.org/10.1038/s41577-019-0180-1

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