The role of the T cell in age-related inflammation

Macaulay, R.; Akbar, Arne N.; Henson, Sian M.

doi:10.1007/s11357-012-9381-2

Cited by 105 publications

(85 citation statements)

References 113 publications

(57 reference statements)

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“…These cells are highly cytotoxic and high in granzyme and perforin expression but could simultaneously express high level of proinflammatory cytokines including IFN-γ and TNF-α (Chiu et al 2016). Production of pro-inflammatory cytokines in turn activates p38 in T cells, inhibits T cell telomerase activity, and promotes loss of CD28 and T cell differentiation, further creating a vicious cycle of immunosenescence (Macaulay et al 2013). CMVspecific T cells are found to express high levels of CX3CR1, which binds to injuried vascular endothelium-expressing fractalkine, and the β2-adrenergic receptor, which permits rapid response toward stress (Pachnio et al 2016;van de Berg et al 2012).…”

Section: And Atherosclerotic Cardiovascular Complicationsmentioning

confidence: 99%

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

2017

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Cytomegalovirus (CMV) is an important pathogen for both clinical and population settings. There is a growing body of research implicating CMV in multiple health outcomes across the life course. At the same time, there is mounting evidence that individuals living in poverty are more likely to be exposed to CMV and more likely to experience many of the chronic conditions for which CMV has been implicated. Further research on the causal role of CMV for health and wellbeing is needed. However, the strong evidence implicating CMV in type 2 diabetes, autoimmunity, cancer, cardiovascular disease, vaccination, and age-related alterations in immune function warrants clinical and public health action. This imperative is even higher among individuals living in socioeconomically disadvantaged settings and those exposed to high levels of chronic psychosocial stress.

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Section: And Atherosclerotic Cardiovascular Complicationsmentioning

confidence: 99%

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

2017

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“…A key role of pTreg cells has been established in models of oral tolerance [3], colitis [4], transplantation [5,6], and in pregnancy [7,8] in which pTreg cells allow the development of a suppressive T-cell repertoire adapted to evolving antigens encountered in the periphery. Aging is associated with altered immune responses to vaccination, infection, cancer, and dysregulation of inflammatory responses [9,10]. In addition to a decrease in naïve T-cell numbers due to thymus involution [11,12], functional impairment of T cells is a major component of the defective immune response in the elderly [13].…”

Section: Foxp3mentioning

confidence: 99%

Extrathymic induction of Foxp3⁺ regulatory T cells declines with age in a T‐cell intrinsic manner

et al. 2013

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Extrathymically induced Foxp3+ regulatory T (Treg) cells contribute to the pool of Treg cells and are implicated in the maintenance of immune tolerance at environmental interfaces. The impact of T-cell senescence on their generation and function is, however, poorly characterized. We report here that steady-state induction of Foxp3 is impaired in aged T cells in vivo. In vitro assays further revealed that this defective generation of Treg cells was independent from the strength of TCR stimulation and arose before T-cell proliferation. Importantly, they also revealed that this impairment of Foxp3 induction is unrelated to known age-related T-cell defects, such as IL-2 secretion impairment, accumulation of activated T-cell populations, or narrowing of the T-cell repertoire. Finally, a loss of extrathymic induction of Foxp3 and tolerance to minor-mismatched skin graft were observed in aged mice treated by nondepleting anti-CD4 antibody. The T-cell intrinsic impairment of Treg-cell generation revealed here highlights age as a key factor to be considered in immune tolerance induction. [5,6], and in pregnancy [7,8] in which pTreg cells allow the development of a suppressive T-cell repertoire adapted to evolving antigens encountered in the periphery. Aging is associated with altered immune responses to vaccination, infection, cancer, and dysregulation of inflammatory responses [9,10]. In addition to a decrease in naïve T-cell numbers due to thymus involution [11,12], functional impairment of T cells is a major component of the defective immune response in the elderly [13]. In particular, an early and transient IL-2 secretion defect in aged T cells leads to impaired proliferation and differentiation in fully functional Th1 and Th2 cells [14,15]. We characterized here the effect of T-cell senescence on pTreg-cell generation and report that T-cell intrinsic defects oppose the induction of Foxp3 in aged Tconv cells both at the steady state and during induction of transplantation tolerance. Results and discussion Impaired Foxp3 induction in vivo at the steady state in aged T cellsTo explore whether T-cell senescence affects pTreg production, we first compared in vivo Foxp3 induction at the steady state in Tconv populations isolated from either young (5-20 weeks) or old (60-65 weeks) Foxp3-eGFP mice. Highly purified CD4 + eGFP − T cells (>99.99%) from young Foxp3-eGFP mice ( Fig. 1A) were transferred into C57Bl/6 CD45.1 + congenic hosts, and 4 weeks after transfer, 0.4% of eGFP + cells was detected in the donor T-cell population (Fig. 1B). In contrast, a 1. A straightforward explanation for the defective pTreg-cell production observed in aged mice could be the progressive disappearance from the periphery of recent thymic emigrants (RTE) enriched in pTreg-cell precursors [17,18]. Precise time-course experiments effectively revealed that pTreg-cell generation was higher in 2-week Tconv cells, which are enriched in RTE, and comparable with that of thymocytes (Fig. 1D). This is consistent with an RTE-dependent conversion process...

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“…Immune senescence results from defects in T‐cell immunity and is also characterized by a low‐grade chronic inflammatory state (Macaulay et al ., 2013). Little is known about the source of the inflammation that fuels most age‐related diseases; however, it may derive from an age‐related decline in homoeostatic immune function, resistance to endogenous microbes or senescent cells (Tchkonia et al ., 2013).…”

Section: Introductionmentioning

confidence: 99%

Human CD8⁺EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK

et al. 2017

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SummaryCellular senescence is accompanied by a senescence‐associated secretory phenotype (SASP). We show here that primary human senescent CD8+ T cells also display a SASP comprising chemokines, cytokines and extracellular matrix remodelling proteases that are unique to this subset and contribute to age‐associated inflammation. We found the CD8+ CD45RA + CD27− EMRA subset to be the most heterogeneous, with a population aligning with the naïve T cells and another with a closer association to the effector memory subset. However, despite the differing processes that give rise to these senescent CD8+ T cells once generated, they both adopt a unique secretory profile with no commonality to any other subset, aligning more closely with senescence than quiescence. Furthermore, we also show that the SASP observed in senescent CD8+ T cells is governed by p38 MAPK signalling.

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The role of the T cell in age-related inflammation

Cited by 105 publications

References 113 publications

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

Extrathymic induction of Foxp3⁺ regulatory T cells declines with age in a T‐cell intrinsic manner

Human CD8⁺EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK

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The role of the T cell in age-related inflammation

Cited by 105 publications

References 113 publications

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

Extrathymic induction of Foxp3+ regulatory T cells declines with age in a T‐cell intrinsic manner

Human CD8+EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK

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Extrathymic induction of Foxp3⁺ regulatory T cells declines with age in a T‐cell intrinsic manner

Human CD8⁺EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK