How age and infection history shape the antigen‐specific CD8<sup>+</sup> T‐cell repertoire: Implications for vaccination strategies in older adults

Lanfermeijer, Josien; Borghans, José A. M.; Baarle, Debbie van

doi:10.1111/acel.13262

Cited by 20 publications

(19 citation statements)

References 128 publications

(215 reference statements)

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“…Altogether, the available evidence suggests that both T cellintrinsic and T cell-extrinsic factors contribute to a reduction in TCR diversity (particularly pronounced in the CD8 + T effector memory CD45RA + (T EMRA ) subset) that compromises immune function and/or causes the disproportionate expansion of T cells specific for autoantigens or antigens encoded by persistent viruses (such as CMV and Epstein-Barr virus). This reduction in TCR diversity has been observed both in longitudinal and cross-sectional population studies 88 .…”

Section: Reduction Of Tcr Repertoirementioning

confidence: 60%

Hallmarks of T cell aging

2021

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ge erodes every physiological function and affects most, if not all, cell types of our body through a series of mechanisms that range from the loss of genomic stability and epigenetic alterations to the loss of proteostasis, deficient nutrient signaling, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and deviant intercellular communication. Most of these 'hallmarks of aging' 1 have been defined in non-vertebrate animal models (such as nematodes and flies) that lack sophisticated adaptive immune systems, suggesting that the principal mechanisms of aging would precede the evolution of B and T lymphocytes and thus relegating these cell types to homeostatic functions that are not central to the core of the aging process.Notwithstanding this conceptual construction, there is ample evidence in mice that T lymphocytes undergo major age-dependent changes that gradually compromise their physiological function, correlating with, and perhaps even explaining, the tendency to develop autoimmune, autoinflammatory, infectious, and malignant diseases in late life 2 . Thus, T cell aging may be one of the principal manifestations of 'immunosenescence' , the time-dependent loss of immune-system vigor that compromises the elimination of noxious elements (such as microbes or malignant cells) while increasing unwarranted overreactions that lead to autoinflammatory and autoimmune disease 3 . Reflecting the fact that circulating (and, to a lesser degree, tumor-infiltrating) T lymphocytes are among the rare cell types that are easily accessible to biomedical investigation, abundant data from humans corroborate the idea that T lymphocytes undergo an important functional deterioration as health declines, placing this cell type in the limelight of human aging research 4 .Recent experiments performed in mice reveal that genetic strategies to accelerate T cell aging, such as the T lymphocyte-specific knockout of the mitochondrial transcription factor A (TFAM), causes not only an immunometabolic dysfunction that drives T cell senescence, but also a general, body-wide deterioration of health with multiple aging-related features, including metabolic, musculoskeletal, cardiovascular, and cognitive alterations 5 . Thus, premature

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Section: Reduction Of Tcr Repertoirementioning

confidence: 60%

Hallmarks of T cell aging

2021

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“…However, the recent finding that only a very small percentage of individuals seroconvert for CMV at later age (Samson et al, 2020 ), as well as the finding that more than 90% of the population is infected with EBV during adolescence (Balfour et al, 2013 ; Winter et al, 2020 ), makes this explanation unlikely. In our view, a more likely explanation for the reduced diversity in the antigen-specific T-cell repertoire of older individuals would be that older individuals have been infected for a longer time, and have lost more T-cell clones over time, for example due to exhaustion after restimulation (Lanfermeijer et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with this, several cross-sectional studies into the CMV and EBV-specific T-cell repertoires reported similar Vβ-skewing in young and older adults, and even identical TCR sequences between individuals of different age groups (Khan et al, 2002 ; Schwanninger et al, 2008 ; Cardenas Sierra et al, 2014 ). Although these studies have led to the view that antigen-specific T-cell repertoires are rather stable with age, it remains unknown, if the diversity of antigen-specific T-cell repertoires is maintained (Lanfermeijer et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…Studies in humans showed similarly contradicting results: while one study showed that CMV + individuals had lower absolute numbers of EBV-specific T cells than CMV − individuals (Khan et al, 2004 ), another study found that the diversity of the non-CMV-specific memory T-cell repertoire was comparable in CMV − and CMV + individuals, thereby suggesting that the memory T-cell pool simply expands to accommodate the large frequencies of CMV-specific T cells (Lindau et al, 2019 ). Thus, the effect of CMV infection on non-CMV-specific T-cell responses and their repertoire diversity, and how this is linked to aging, remains poorly understood (Lanfermeijer et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Age and CMV-Infection Jointly Affect the EBV-Specific CD8+ T-Cell Repertoire

et al. 2021

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CD8+ T cells play an important role in protection against viral infections. With age, changes in the T-cell pool occur, leading to diminished responses against both new and recurring infections in older adults. This is thought to be due to a decrease in both T-cell numbers and T-cell receptor (TCR) diversity. Latent infection with cytomegalovirus (CMV) is assumed to contribute to this age-associated decline of the immune system. The observation that the level of TCR diversity in the total memory T-cell pool stays relatively stable during aging is remarkable in light of the constant input of new antigen-specific memory T cells. What happens with the diversity of the individual antigen-specific T-cell repertoires in the memory pool remains largely unknown. Here we studied the effect of aging on the phenotype and repertoire diversity of CMV-specific and Epstein-Barr virus (EBV)-specific CD8+ T cells, as well as the separate effects of aging and CMV-infection on the EBV-specific T-cell repertoire. Antigen-specific T cells against both persistent viruses showed an age-related increase in the expression of markers associated with a more differentiated phenotype, including KLRG-1, an increase in the fraction of terminally differentiated T cells, and a decrease in the diversity of the T-cell repertoire. Not only age, but also CMV infection was associated with a decreased diversity of the EBV-specific T-cell repertoire. This suggests that both CMV infection and age can impact the T-cell repertoire against other antigens.

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“…That cells age is irrefutable ( 36 – 38 ). For instance, cellular aging has implications in cancer ( 37 – 41 ), and vaccination of the elderly is affected by the poor responsiveness of their aged T cells ( 40 – 47 ). Yet, due consideration has not been given to the aging of cells in models of memory T-cell homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Effect of cellular aging on memory T-cell homeostasis

2022

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The fact that T-cell numbers remain relatively stable throughout life, and that T-cell proliferation rates increase during lymphopenia, has led to the consensus that T-cell numbers are regulated in a density-dependent manner. Competition for resources among memory T cells has been proposed to underlie this ‘homeostatic’ regulation. We first review how two classic models of resource competition affect the T-cell receptor (TCR) diversity of the memory T-cell pool. First, ‘global’ competition for cytokines leads to a skewed repertoire that tends to be dominated by the very first immune response. Second, additional ‘cognate’ competition for specific antigens results in a very diverse and stable memory T-cell pool, allowing every antigen to be remembered, which we therefore define as the ‘gold-standard’. Because there is limited evidence that memory T cells of the same specificity compete more strongly with each other than with memory T cells of different specificities, i.e., for ‘cognate’ competition, we investigate whether cellular aging could account for a similar level of TCR diversity. We define cellular aging as a declining cellular fitness due to reduced proliferation. We find that the gradual erosion of previous T-cell memories due to cellular aging allows for better establishment of novel memories and for a much higher level of TCR diversity compared to global competition. A small continual source (either from stem-cell-like memory T-cells or from naive T-cells due to repeated antigen exposure) improves the diversity of the memory T-cell pool, but remarkably, only in the cellular aging model. We further show that the presence of a source keeps the inflation of chronic memory responses in check by maintaining the immune memories to non-chronic antigens. We conclude that cellular aging along with a small source provides a novel and immunologically realistic mechanism to achieve and maintain the ‘gold-standard’ level of TCR diversity in the memory T-cell pool.

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How age and infection history shape the antigen‐specific CD8⁺ T‐cell repertoire: Implications for vaccination strategies in older adults

Cited by 20 publications

References 128 publications

Hallmarks of T cell aging

Hallmarks of T cell aging

Age and CMV-Infection Jointly Affect the EBV-Specific CD8+ T-Cell Repertoire

Effect of cellular aging on memory T-cell homeostasis

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How age and infection history shape the antigen‐specific CD8+ T‐cell repertoire: Implications for vaccination strategies in older adults

Cited by 20 publications

References 128 publications

Hallmarks of T cell aging

Hallmarks of T cell aging

Age and CMV-Infection Jointly Affect the EBV-Specific CD8+ T-Cell Repertoire

Effect of cellular aging on memory T-cell homeostasis

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How age and infection history shape the antigen‐specific CD8⁺ T‐cell repertoire: Implications for vaccination strategies in older adults