Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK+ CD8+ T Cells as Conserved Hallmark of Inflammaging

Mogilenko, Denis A.; Shpynov, Oleg; Andhey, Prabhakar S.; Arthur, Laura L.; Swain, Amanda; Esaulova, Ekaterina; Brioschi, Simone; Shchukina, Irina; Kerndl, Martina; Bambousková, Monika; Yao, Zhangting; Laha, Anwesha; Zaitsev, Konstantin; Burdess, Samantha; Gillfilan, Susan; Stewart, Sheila A.; Colonna, Marco; Artyomov, Maxim N.

doi:10.1016/j.immuni.2020.11.005

Cited by 354 publications

(404 citation statements)

References 55 publications

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“…Indeed, phenotypic analyses revealed an age-associated reduction in the proportion and numbers of naive T cells in humans, non-human primates, and mice (154)(155)(156)(157)(158). Recent comprehensive single-cell transcriptional profiling studies confirm the shift towards a higher frequency of effector-memory T cell subsets with age (159,160). Notably, in mice, aging was associated with a stark increase in representation of cytotoxic CD4+ T cells, exhausted CD4+ T cells, and activated Treg (159).…”

Section: Declining Function Of Tconv Cells During Agingmentioning

confidence: 99%

Age-Related Changes in Thymic Central Tolerance

et al. 2021

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Thymic epithelial cells (TECs) and hematopoietic antigen presenting cells (HAPCs) in the thymus microenvironment provide essential signals to self-reactive thymocytes that induce either negative selection or generation of regulatory T cells (Treg), both of which are required to establish and maintain central tolerance throughout life. HAPCs and TECs are comprised of multiple subsets that play distinct and overlapping roles in central tolerance. Changes that occur in the composition and function of TEC and HAPC subsets across the lifespan have potential consequences for central tolerance. In keeping with this possibility, there are age-associated changes in the cellular composition and function of T cells and Treg. This review summarizes changes in T cell and Treg function during the perinatal to adult transition and in the course of normal aging, and relates these changes to age-associated alterations in thymic HAPC and TEC subsets.

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Section: Declining Function Of Tconv Cells During Agingmentioning

confidence: 99%

Age-Related Changes in Thymic Central Tolerance

et al. 2021

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“…This impacts the circulatory T cell compartment as there are fewer recent thymic emigrants seeding secondary lymphoid tissue. For unknown reasons, this affects the diversity of the naïve CD8 compartment more than the CD4 T cell compartment (81). Thus, with age, CD8 memory T cells are enriched and TCR repertoires are likely narrowed across tissues (80)(81)(82)(83)(84)(85).…”

Section: Altered Immune Homeostasis In Advanced Agementioning

confidence: 99%

“…For unknown reasons, this affects the diversity of the naïve CD8 compartment more than the CD4 T cell compartment (81). Thus, with age, CD8 memory T cells are enriched and TCR repertoires are likely narrowed across tissues (80)(81)(82)(83)(84)(85). Notably, if memory CD8 T cells are formed early in life, they likely provide life-long diverse secondary responses (86,87).…”

Section: Altered Immune Homeostasis In Advanced Agementioning

confidence: 99%

“…While viral-specific pathogenic CD8 T cells have not been found in human tissue to-date, plausible candidates may now be on the radar. Age-associated granzyme K-expressing CD8 T cells are enriched in the T effector memory compartment in human blood (81). Age-associated CD8 T cell counterparts in mice were identified by expression of the effector molecule granzyme K, the checkpoint molecule PD-1, integrin CD49d, and the transcription factor TOX and are enriched in blood and across tissues (spleen, peritoneum, lungs, liver, and white adipose tissue) with age.…”

Section: The Aged Environment Provokes Malfunctional Cd8 T Rm Cell Acmentioning

confidence: 99%

“…It's unclear how granzyme K + age-associated CD8 T cells behave in an immune response. While their phenotype (PD-1 Hi TOX + ) is typically associated with CD8 T cell exhaustion, recombinant granzyme K augmented cytokine and chemokine production from senescent fibroblasts in vitro (81). Activation of local ageassociated CD8 T cells may thus provoke inflammation and potentially influence tissue remodeling and senescence associated secretion phenotypes.…”

Section: The Aged Environment Provokes Malfunctional Cd8 T Rm Cell Acmentioning

confidence: 99%

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Age-Related Dynamics of Lung-Resident Memory CD8+ T Cells in the Age of COVID-19

2021

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Following respiratory viral infections or local immunizations, lung resident-memory T cells (TRM) of the CD8 lineage provide protection against the same pathogen or related pathogens with cross-reactive T cell epitopes. Yet, it is now clear that, if homeostatic controls are lost following viral pneumonia, CD8 TRM cells can mediate pulmonary pathology. We recently showed that the aging process can result in loss of homeostatic controls on CD8 TRM cells in the respiratory tract. This may be germane to treatment modalities in both influenza and coronavirus disease 2019 (COVID-19) patients, particularly, the portion that present with symptoms linked to long-lasting lung dysfunction. Here, we review the developmental cues and functionalities of CD8 TRM cells in viral pneumonia models with a particular focus on their capacity to mediate heterogeneous responses of immunity and pathology depending on immune status.

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Single‐Cell Transcriptomics Reveals Longevity Immune Remodeling Features Shared by Centenarians and Their Offspring

et al. 2022

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Centenarians, who show mild infections and low incidence of tumors, are the optimal model to investigate healthy aging. However, longevity related immune characteristics has not been fully revealed largely due to lack of appropriate controls. In this study, single-cell transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) derived from seven centenarians (CEN), six centenarians' offspring (CO), and nine offspring spouses or neighbors (Control, age-matched to CO) are performed to investigate the shared immune features between CEN and CO. The results indicate that among all 12 T cell clusters, the cytotoxic-phenotype-clusters (CPC) and the naïve-phenotype-clusters (NPC) significantly change between CEN and ontrol. Compared to Control, both CEN and CO are characterized by depleted NPC and increased CPC, which is dominated by CD8 + T cells. Furthermore, CPC from CEN and CO share enhanced signaling pathways and transcriptional factors associated with immune response, and possesse similar T-cell-receptor features, such as high clonal expansion. Interestingly, rather than a significant increase in GZMK + CD8 cells during aging, centenarians show accumulation of GZMB + and CMC1 + CD8 T cells. Collectively, this study unveils an immune remodeling pattern reflected by both quantitative increase and functional reinforcement of cytotoxic T cells which are essential for healthy aging.

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Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK+ CD8+ T Cells as Conserved Hallmark of Inflammaging

Cited by 354 publications

References 55 publications

Age-Related Changes in Thymic Central Tolerance

Age-Related Changes in Thymic Central Tolerance

Age-Related Dynamics of Lung-Resident Memory CD8+ T Cells in the Age of COVID-19

Single‐Cell Transcriptomics Reveals Longevity Immune Remodeling Features Shared by Centenarians and Their Offspring

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