Epigenetics of T cell aging

Goronzy, Jörg J.; Hu, Bin; Kim, Chulwoo; Jadhav, Rohit R.; Weyand, Cornelia M.

doi:10.1002/jlb.1ri0418-160r

Cited by 47 publications

(43 citation statements)

References 88 publications

(189 reference statements)

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“…Our data on TF networks in naïve CD4 T cells are consistent with the concept that immune aging involves the activation of T‐cell differentiation pathways resulting in a loss of naivety and stemness (Goronzy et al, ). Throughout adult life, the T‐cell compartment is maintained by homeostatic proliferation that is under the control of cytokines as well as requires survival signals from TCR (Goronzy & Weyand, ; Yanes, Gustafson, Weyand, & Goronzy, ).…”

Section: Discussionsupporting

confidence: 89%

“…Epigenetic studies of human CD8 T cells have provided evidence for loss of stemness as indicated by increased accessibility for bZIP transcription factors with age, a signature that is also a hallmark of differentiation (Moskowitz et al, ; Ucar et al, ). A similar but less pronounced trend is seen for naïve CD4 T cells (Goronzy, Hu, Kim, Jadhav, & Weyand, ). T‐cell phenotypic changes indicating an altered composition with age include the loss of CD31, CR1, and CR2 and the gain of CD25 in subsets of naïve CD4 T cells (den Braber et al, ; Kohler & Thiel, ; Pekalski et al, ).…”

Section: Introductionsupporting

confidence: 58%

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Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Li²,

Ye³

et al. 2019

Aging Cell

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With reduced thymic activity, the population of naïve T cells in humans is maintained by homeostatic proliferation throughout adult life. In young adults, naïve CD4 T cells have enormous proliferative potential and plasticity to differentiate into different lineages. Here, we explored whether naïve CD4 T‐cell aging is associated with a partial loss of this unbiased multipotency. We find that naïve CD4 T cells from older individuals have developed a propensity to develop into TH9 cells. Two major mechanisms contribute to this predisposition. First, responsiveness to transforming growth factor β (TGFβ) stimulation is enhanced with age due to an upregulation of the TGFβR3 receptor that results in increased expression of the transcription factor PU.1. Secondly, aged naïve CD4 T cells display altered transcription factor profiles in response to T‐cell receptor stimulation, including enhanced expression of BATF and IRF4 and reduced expression of ID3 and BCL6. These transcription factors are involved in TH9 differentiation as well as IL9 transcription suggesting that the aging‐associated changes in the transcription factor profile favor TH9 commitment.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionsupporting

confidence: 58%

Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Li²,

Ye³

et al. 2019

Aging Cell

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“…Loss of polyfunctionality may be a consequence of more progressed or end-differentiation, as indicated by the chromatin state of old central memory T cells or the increased frequencies of terminally differentiated effector memory cells (TEMRAs). 130 An alternative explanation is that memory T cells in older individuals respond qualitatively differently to TCR stimulation than in young. Indeed, similar to naive T cells, memory CD8 T cells display reduced miR-181a, which likely reduces some TCRmediated signals.…”

Section: Aging Tissue Microenvironment As a Blockade To Effective Primentioning

confidence: 99%

Influence of immune aging on vaccine responses

Gustafson

Kim

Weyand

et al. 2020

Journal of Allergy and Clinical Immunology

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210

177

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Impaired vaccine responses in older individuals are associated with alterations in both the quantity and quality of the T-cell compartment with age. As reviewed herein, the T-cell response to vaccination requires a fine balance between the generation of inflammatory effector T cells versus follicular helper T (T FH) cells that mediate high-affinity antibody production in tandem with the induction of longlived memory cells for effective recall immunity. During aging, we find that this balance is tipped where T cells favor short-lived effector but not memory or T FH responses. Consistently, vaccine-induced antibodies commonly display a lower protective capacity. Mechanistically, multiple, potentially targetable, changes in T cells have been identified that contribute to these age-related defects, including posttranscription regulation, T-cell receptor signaling, and metabolic function. Although research into the induction of tissue-specific immunity by vaccines and with age is still limited, current mechanistic insights provide a framework for improved design of age-specific vaccination strategies that require further evaluation in a clinical setting. (

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“…With the exception of these effector T cells that are frequently specific for latent viruses, unstimulated circulating naïve and memory CD4 + and CD8 + T cells do not show evidence of cellular senescence that could account for age-associated immune defects (8). Rather than senescence-associated defects, epigenetic signatures and microRNA profiles induced by T cell aging are indicative of activated differentiation pathways that favor development into short-lived effector cells (9).…”

Section: Introductionmentioning

confidence: 99%

FOXO1 deficiency impairs proteostasis in aged T cells

Jin

et al. 2020

Sci. Adv.

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T cell differentiation involves the dynamic regulation of FOXO1 expression, which rapidly declines after activation and is subsequently restored. Reexpression is impaired in naïve CD4+ T cell responses from older individuals. Here, we show that FOXO1 promotes lysosome function through the induction of the key transcription factor for lysosomal proteins, TFEB. Subdued FOXO1 reexpression in activated CD4+ T cells impairs lysosomal activity, causing an expansion of multivesicular bodies (MVBs). Expansion of the MVB compartment induces the sequestration of glycogen synthase kinase 3β (GSK3β), thereby suppressing protein turnover and enhancing glycolytic activity. As a consequence, older activated CD4+ T cells develop features reminiscent of senescent cells. They acquire an increased cell mass, preferentially differentiate into short-lived effector T cells, and secrete exosomes that harm cells in the local environment through the release of granzyme B.

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Epigenetics of T cell aging

Cited by 47 publications

References 88 publications

Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Influence of immune aging on vaccine responses

FOXO1 deficiency impairs proteostasis in aged T cells

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