The narrowing of the CD8 T cell repertoire in old age

Blackman, Marcia A.; Woodland, David L.

doi:10.1016/j.coi.2011.05.005

Cited by 92 publications

(75 citation statements)

References 49 publications

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“…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].…”

Section: Extrathymically Induced 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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Section: Extrathymically Induced 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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“…From animal experiments, it has been suggested that the diversity of the immune receptor repertoire critically governs primary immune responses against pathogens (11)(12)(13).…”

Section: Reduced Initial Naive Cd8mentioning

confidence: 99%

“…Fifty milliliters of venous blood was drawn immediately before vaccination (day 0) and at eight further time points [days 2 (only donors 15-27), 4, 7, 10, 14, 17, 21, and 28] after vaccination into sodium heparin, serum gel, or EDTA tubes (BD Biosciences, Plymouth, U.K.). The study was run in three individual rounds [round I (donors 1-6), round II (donors [8][9][10][11][12][13][14], and round III (donors 15-27, additional study day 2)] and the obtained data sets were cross-checked for variability between runs before being merged for analysis. To study long-term YF-specific memory formation and stability, we collected in each case 50 ml venous blood from 19 of 23 vaccinees reinvited 33 (donors 1-6), 30 (donors [8][9][10][11][12][13][14], or 20 (donors 15-27) months after vaccination.…”

Section: Vaccination and Study Cohortmentioning

confidence: 99%

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Low Thymic Activity and Dendritic Cell Numbers Are Associated with the Immune Response to Primary Viral Infection in Elderly Humans

Schulz

Mälzer

Domingo

et al. 2015

The Journal of Immunology

108

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Immunological competence declines progressively with age, resulting in increased susceptibility of the elderly to infection and impaired responses to vaccines. Underlying mechanisms remain largely obscure as they have been related to complex, individual systemic immune properties that are challenging to investigate. In this study, we explored age-related changes in human immunity during a primary virus infection experimentally induced by immunization with live-attenuated yellow fever (YF) vaccine. Applying detailed serology, advanced FACS analysis, and systems biology, we discovered that aged subjects developed fewer neutralizing Abs, mounted diminished YF-specific CD8+ T cell responses, and showed quantitatively and qualitatively altered YF-specific CD4+ T cell immunity. Among numerous immune signatures, low in vivo numbers of naive CD4+ recent thymic emigrants and peripheral dendritic cells correlated well with reduced acute responsiveness and altered long-term persistence of human cellular immunity to YF vaccination. Hence, we reveal in this article that essential elements of immune responses such as recent thymic emigrants and dendritic cells strongly relate to productive immunity in the elderly, providing a conceivable explanation for diminished responsiveness to vaccination with neoantigens and infection with de novo pathogens in the aged population.

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“…This reduces the diversity of the repertoire (Ahmed, Lanzer et al 2009), decreases the potential to drive an immune response and affects the CD4/CD8 ratio (LeMaoult, Messaoudi et al 2000;Messaoudi, Lemaoult et al 2004 ;Clambey, van Dyk et al 2005;Goronzy and Weyand 2005;Pawelec, Akbar et al 2005;Clambey, Kappler et al 2007) reviewed in (Blackman and Woodland 2011). With age CD4 T cells have increased longevity (Tsukamoto, Clise-Dwyer et al 2009) while under normal homeostatic conditions recent thymic migrant have to compete with already established mature naïve T cells (Houston, Higdon et al 2011).…”

mentioning

confidence: 99%

Immunodepression and Immunosuppression During Aging

Thomas‐Vaslin¹,

Six²,

Pham³

et al. 2012

Immunosuppression - Role in Health and Diseases

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The narrowing of the CD8 T cell repertoire in old age

Cited by 92 publications

References 49 publications

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

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

Low Thymic Activity and Dendritic Cell Numbers Are Associated with the Immune Response to Primary Viral Infection in Elderly Humans

Immunodepression and Immunosuppression During Aging

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The narrowing of the CD8 T cell repertoire in old age

Cited by 92 publications

References 49 publications

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

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

Low Thymic Activity and Dendritic Cell Numbers Are Associated with the Immune Response to Primary Viral Infection in Elderly Humans

Immunodepression and Immunosuppression During Aging

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Resources

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

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